Benzimidazole derivatives and their use as GnRH antagonists

ABSTRACT

A subject of the present application is new benzimidazole derivatives of formula 
                         
in which A, Y, R 1 , R 2 , R 3  and R 4  represent different variable groups. These products have an antagonist activity of GnRH (Gonadotropin-Releasing Hormone). The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.

A subject of the present application is new benzimidazole derivatives(amino- and thio-benzimidazoles. These products possess an agonistactivity of GnRH (Gonadotropin-Releasing Hormone). The invention alsorelates to pharmaceutical compositions containing said products andtheir use for the preparation of a medicament.

GnRH (Gonadotropin-Releasing Hormone), also called LHRH(Luteinizing-Hormone-Releasing Hormone) is a hypothalamic decapeptide(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) which regulates thereproduction system in vertebrates. It is released into the capillariesof the hypothalamus-hypophyseal portal system of the median eminence andof the infundibular stalk. By this network it reaches the anteriorpituitary lobe and reaches, via a second capillary network, thegonadotropic target cell. GnRH acts at the level of the membrane of thetarget cells, via receptors with seven transmembrane segments coupled tophospholipase C via G proteins leading to an increase of intracellularcalcium flux. Its action induces biosynthesis and the release of thegonadotropic hormones FSH (follicle-stimulating hormone) and LH(luteinizing hormone). GnRH agonists and antagonists have proven to beeffective in women in the treatment of endometriosis, fibroma,polycystic ovary syndrome, cancer of the breast, ovary and endometrium,gonadotropic hypophyseal desensitization during medically assistedprocreation protocols; in man, in the treatment of benign prostatichyperplasia and cancer of the prostate; and in the treatment of male orfemale precocious puberty.

The GnRH antagonists currently used are peptide compounds whichgenerally must be administered by intravenous or sub-cutaneous routebecause of their poor oral bioavailability. The non-peptide antagonistsof GnRH, which present the advantage of being able to be administered byoral route, are the subject of numerous research efforts. For example,non-peptide GnRH antagonist compounds were described in J. Med. Chem,41, 4190-4195 (1998) and Bioorg. Med. Chem. Lett, 11, 2597-2602 (2001).

The present invention relates to a new family of powerful non-peptideGnRH antagonist compounds.

A subject of the invention is therefore a compound of general formula(1)

in racemic, enantiomeric form or any combination of these forms and inwhich:

-   A represents —CH₂— or —C(O)—;-   Y represents —S— or —NH—;-   R₁ and R₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl, a (C₅-C₉)bicycloalkyl optionally substituted by one or    more identical or different (C₁-C₆)alkyl radicals, or a radical of    formula —(CH₂)_(n)—X in which    -   X represents amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino,        (C₃-C₇)cycloalkyl, adamantyl, heterocycloalkyl, aryl,        aryl-carbonyl or heteroaryl, or a radical of formula

-   -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n′)—X′—Y′, halo,        oxo, nitro, cyano, amino, (C₁-C₆)alkylamino and        di((C₁-C₈)alkyl)amino, hydroxy, N₃;    -   X′ represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—, —NH—SO₂— or        a covalent bond;    -   Y′ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals; heteroaryl or        aryl or heterocycloalkyl optionally substituted by one or more        identical or different substituents chosen from: (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, halo, nitro, cyano, amino, CF₃, OCF₃, hydroxy,        N₃, (C₁-C₆)alkylamino and di((C₁-C₈)alkyl)amino;    -   n represents an integer from 0 to 6 and n′ an integer from 0 to        2;    -   or R₁ and R₂ form together, with the nitrogen atom to which they        are attached, a heterocycloalkyl, a heterobicycloalkyl or a        radical of formula:

-   -   the radical formed by R₁ and R₂ together being optionally        substituted by one or more identical or different substituents        chosen from:        -   —(CH₂)_(n″)—X″—Y″, oxo, hydroxy, halo, nitro, cyano;        -   X″ represents —O—, —C(O)—, —C(O)—O— or a covalent bond;        -   Y″, represents a (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,            di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl, heterocycloalkyl,            arylalkyl radical, or aryl or heteroaryl radical optionally            substituted by one or more identical or different            substituents chosen from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy,            (C₁-C₆)alkyl-carbonyl, halo, hydroxy, nitro, cyano, CF₃,            OCF₃, amino, (C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino);            or a radical of formula

-   -   -   n″ represents an integer from 0 to 4;

-   R₃ represents —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃    -   W₃ represents a covalent bond, —CH(OH)— or —C(O)—;    -   Z₃ represents a (C₁-C₆)alkyl, adamantyl, aryl radical, a        heteroaryl, or a radical of formula

-   -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from:        —(CH₂)_(p″)—V₃—Y₃, halo, nitro, cyano, N₃, hydroxy;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂— or a covalent        bond;    -   Y₃ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo radicals, amino,        (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, phenylcarbonylmethyl,        heterocycloalkyl or aryl radicals;    -   p, p′ and p″ represent, independently, an integer from 0 to 4;

-   R₄ represents a radical of formula-(CH₂)_(s)—R″₄    -   R″₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl or        aralkyl; a heteroaryl containing at least one nitrogen atom and        optionally substituted by (C₁-C₆)alkyl; or a radical of formula        —NW₄W′₄    -   W₄ represents the hydrogen atom, (C₁-C₈)alkyl or        (C₃-C₇)cycloalkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;    -   Q₄ represents a covalent bond,        —CH₂—CH(OH)—[CH₂]_(t)—[O]_(t′)—[CH₂]_(t″)-or —C(O)—O—;    -   t, t′ and t″ represent, independently, 0 or 1;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally        substituted by one or more identical or different substituents        chosen from: (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkyldithio        and hydroxy; (C₂-C₆)alkenyl; (C₂-C₆)alkynyl; (C₃-C₇)cycloalkyl        optionally substituted by one or more identical or different        substituents chosen from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy-carbonyl        and (C₁-C₆)hydroxyalkyl; cyclohexene; adamantyl; heteroaryl;        aryl optionally substituted by one or more identical or        different radicals chosen from formula —(CH₂)_(q″)—V₄—Y₄,        hydroxy, halo, nitro, cyano;        -   V₄ represents —O—, —S—, —NH—C(O)— or a covalent bond;        -   Y₄ represents a (C₁-C₆)alkyl radical optionally substituted            by di((C₁-C₆)alkyl)amino or one or more identical or            different halo radicals; amino; (C₁-C₆)alkylamino;            di((C₁-C₆)alkyl)amino; aralkyl; heterocycloalkyl radicals;        -   q″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6;        or a pharmaceutically acceptable salt of the latter.

In the definitions indicated above, the expression halo represents thefluoro, chloro, bromo or iodo, preferably chloro, fluoro or bromoradical. The expression alkyl (unless specified otherwise), preferablyrepresents a linear or branched alkyl radical having 1 to 6 carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl,2,2-dimethyl-propyl, hexyl, isohexyl or 1,2,2,-trimethyl-propylradicals. The term (C₁-C₈)alkyl designates a linear or branched alkylradical having 1 to 8 carbon atoms, such as the radicals containing from1 to 6 carbon atoms as defined above but also heptyl, octyl,1,1,2,2-tetramethyl-propyl, 1,1,3,3-tetramethyl-butyl. The termalkyl-carbonyl preferably designates the radicals in which the alkylradical is as defined above such as for example methylcarbonyl andethylcarbonyl. The term hydroxyalkyl designates the radicals in whichthe alkyl radical is as defined above such as for example hydroxymethyl,hydroxyethyl.

By alkenyl, unless specified otherwise, is meant a linear or branchedalkyl radical containing 1 to 6 carbon-atoms and having at least oneunsaturation (double bond), such as for example vinyl, allyl, propenyl,butenyl or pentenyl. By alkynyl, unless specified otherwise, is meant alinear or branched alkyl radical containing 1 to 6 carbon atoms andhaving at least one double unsaturation (triple bond) such as forexample an ethynyl, propargyl, butynyl or pentynyl radical.

The term alkoxy designates the radicals in which the alkyl radical is asdefined above such as for example the methoxy, ethoxy, propyloxy orisopropyloxy radicals but also linear, secondary or tertiary butoxy,pentyloxy. The term alkoxy-carbonyl preferably designates the radicalsin which the alkoxy radical is as defined above such as for examplemethoxycarbonyl, ethoxycarbonyl. The term alkylthio designates theradicals in which the alkyl radical is as defined above such as forexample methylthio, ethylthio. The term alkyldithio preferablydesignates the radicals in which the alkyl radical is as defined abovesuch as for example methyldithio (CH₃—S—S—), ethyldithio orpropyldithio.

The term (C₃-C₇)cycloalkyl designates a saturated carbon monocyclicsystem comprising from 3 to 7 carbon atoms, and preferably thecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.The expression heterocycloalkyl designates a condensed monocyclic orbicyclic saturated system containing from 2 to 7 carbon atoms and atleast one heteroatom. This radical can contain several identical ordifferent heteroatoms. Preferably, the heteroatoms are chosen fromoxygen, sulphur or nitrogen. As an example of heterocycloalkyl, therings containing at least one nitrogen atom such as pyrrolidine,imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine,isoxazolidine, oxazolidine, piperidine, piperazine, azepane, diazepane,morpholine, decahydroisoquinoline but also the rings not containing anitrogen atom such as tetrahydrofuran or tetrahydrothiophene can bementioned.

The term (C₅-C₉)bicycloalkyl designates a non-condensed saturatedhydrocarbon bycyclic system containing from 5 to 9 carbon atoms, such asbicyclo-heptane such as for example bicylo[2,2,1]heptane, orbicyclo-octane such as for example bicyclo[2,2,2]octane orbicyclo[3,2,1]octane. The term heterobicycloalkyl designates anon-condensed saturated hydrocarbon bycyclic system containing 5 to 8carbon atoms and at least one heteroatom chosen from nitrogen, oxygenand sulphur. As an example of a heterobicycloalkyl, aza-bicycloheptaneand aza-bicyclooctane such as 7-aza-bicyclo[2,2,1]heptane,2-aza-bicyclo[2,2,2]octane or 6-aza-bicyclo[3,2,1]octane can bementioned.

The expression aryl represents an aromatic radical, constituted by acondensed ring or rings, such as for example the phenyl, naphthyl orfluorenyl radical. The expression heteroaryl designates an aromaticradical, constituted by a condensed ring or rings, with at least onering containing one or more identical or different heteroatoms chosenfrom sulphur, nitrogen or oxygen. As an example of a heteroaryl radical,the radicals containing at least one nitrogen atom such as pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl,triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl,isoquinolyl, quinoxalinyl, indolyl, benzoxadiazoyl, carbazolyl but alsothe radicals not containing a nitrogen atom such as thienyl,benzothienyl, furyl, benzofuryl or pyranyl can be mentioned.

The term aralkyl (arylalkyl) preferably designates the radicals in whichthe aryl and alkyl radical are as defined above; as an example ofarylalkyl, benzyl, phenethyl, phenylpropyl and phenylbutyl can bementioned. The term aryl-carbonyl preferably designates the radicals inwhich the aryl radical is as defined above, such as for examplephenylcarbonyl.

The terms alkylamino and dialkylamino preferably designate the radicalsin which the alkyl radicals are as defined above, such as for examplemethylamino, ethylamino, dimethylamino, diethylamino or(methyl)(ethyl)amino.

Also in the present application, the (CH₂)_(i) radical (i an integerbeing able to represent n, n′, n″, p, p′, p″, s, s′, s″ and q″″ asdefined above), represents a linear or branched hydrocarbon chain, of icarbon atoms.

A subject of the invention is also a compound of general formula (I′)

in racemic, enantiomeric form or all combinations of these forms and inwhich:

-   A_(a) represents —CH₂— or —C(O)—;-   Y_(a) represents —S— or —NH—;-   R′₁ and R′₂ represent, independently, the hydrogen atom, a    (C₁-C₈)alkyl, a (C₅-C₉)bicycloalkyl radical optionally substituted    by one or more identical or different (C₁-C₆)alkyl radicals, or a    radical of formula —(CH₂)_(n)—X in which    -   X represents, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino,        (C₃-C₇)cycloalkyl, adamantyl, heterocycloalkyl, aryl,        aryl-carbonyl or heteroaryl, or a radical of formula

-   -   the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl        radicals being optionally substituted by one or more identical        or different substituents chosen from: —(CH₂)_(n′)—X′—Y′, halo,        oxo, nitro, cyano, amino, (C₁-C₆)alkylamino and        di((C₁-C₈)alkyl)amino, hydroxy, N₃;    -   X′ represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—, —NH—SO₂— or        a covalent bond;    -   Y′ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo; heteroaryl or aryl or        heterocycloalkyl radicals optionally substituted by one or more        identical or different substituents chosen from: (C₁-C₆)alkyl,        (C₁-C₆)alkoxy, halo, nitro, cyano, amino, CF₃, OCF₃, hydroxy,        N₃, (C₁-C₆)alkylamino and di((C₁-C₈)alkyl)amino;    -   n represents an integer from 0 to 6 and n′ an integer from 0 to        2;    -   or R′₁ and R′₂ form together, with the nitrogen atom to which        they are attached, a heterocycloalkyl, a heterobicycloalkyl or a        radical of formula:

-   -   the radical which R′₁ and R′₂ form together being optionally        substituted by one or more identical or different substituents        chosen from:        -   —(CH₂)_(n″)—X″—Y″, oxo, hydroxy, halo, nitro, cyano;        -   X″ represents —O—, —C(O)—, —C(O)—O— or a covalent bond;        -   Y″ represents a (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,            di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl, heterocycloalkyl,            arylalkyl, or aryl or heteroaryl radical optionally            substituted by one or more identical or different            substituents chosen from: (C₁-C₆)alkyl, (C₁-C₆)alkoxy,            (C₁-C₆)alkyl-carbonyl, halo, hydroxy, nitro, cyano, CF₃,            OCF₃, amino, (C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino);            or a radical of formula

-   -   -   n″ represents an integer from 0 to 4;

-   R′₃ represents —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃    -   W₃ represents a covalent bond, —CH(OH)— or —C(O)—;    -   Z₃ represents a (C₁-C₆)alkyl, adamantyl, aryl, a heteroaryl        radical, or a radical of formula

-   -   the aryl radical being optionally substituted by one or more        identical or different substituents chosen from:        —(CH₂)_(p″)—V₃—Y₃, halo, nitro, cyano, N₃, hydroxy;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂— or a covalent        bond;    -   Y₃ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo, amino,        (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, phenylcarbonylmethyl,        heterocycloalkyl or aryl radicals;    -   p, p′ and p″ represent, independently, an integer from 0 to 4;

-   R′₄ represents a radical of formula —(CH₂)_(s)—R″₄    -   R″₄ represents a heterocycloalkyl containing at least one        nitrogen atom and optionally substituted by (C₁-C₆)alkyl or        aralkyl; a heteroaryl containing at least one nitrogen atom and        optionally substituted by (C₁-C₆)alkyl; or a radical of formula        —NW₄W′₄    -   W₄ represents the hydrogen atom, (C₁-C₈)alkyl or        (C₃-C₇)cycloalkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;    -   Q₄ represents a covalent bond,        —CH₂—CH(OH)—[CH₂]_(t)-[O]_(t′)—[CH₂]_(t″)-or —C(O)—O—;    -   t, t′ and t″ represent, independently, 0 or 1;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl,        (C₃-C₇)cycloalkyl; heteroaryl; aryl optionally substituted by        one or more identical or different radicals chosen from formula        —(CH₂)_(q″)—V₄—Y₄, hydroxy, halo, nitro, cyano;        -   V₄ represents —O—, —S—, —NH—C(O)— or a covalent bond;        -   Y₄ represents a (C₁-C₆)alkyl radical optionally substituted            by di((C₁-C₆)alkyl)amino or one or more identical or            different halo; amino; (C₁-C₆)alkylamino;            di((C₁-C₆)alkyl)amino; aralkyl; heterocycloalkyl radicals;        -   q″ represents an integer from 0 to 4;    -   or Z₄ represents a radical of formula

-   -   s and s′ represent, independently, an integer from 0 to 6;        or a pharmaceutically acceptable salt of the latter.

A more particular subject of the present invention is a compound offormula I or I′ as defined above or a pharmaceutically acceptable saltof the latter, and in which A represents —C(O)—.

A more particular subject of the present invention is a compound offormula I as defined above or a pharmaceutically acceptable salt of thelatter, and in which

-   -   the cycloalkyl that represents X is cyclohexyl or cycloheptyl,    -   the heterocycloalkyl that represents X is chosen from:        piperidine, pyrrolidine, thiazolidine, morpholine and        tetrahydrothiophene;    -   the aryl that represents X is the phenyl, naphthyl or fluorenyl        radical;    -   the aryl of the aryl-carbonyl radical that represents X, is the        phenyl radical;    -   the heteroaryl that represents X is chosen from: pyridine,        imidazole, thiophene, indole, carbazole and isoquinoline;    -   the heteroaryl that represents Y′ is chosen from oxazole and        imidazole;    -   the aryl that represents Y′ is the phenyl radical;    -   the heterocycloalkyl that represents Y′ is piperazine;    -   the heterocycloalkyl that R₁ and R₂ form together with the        nitrogen atom to which they are attached, is chosen from:        piperidine, piperazine, diazepane, thiazolidine and morpholine;    -   the cycloalkyl that represents Y″ is cyclopentyl or cyclohexyl;    -   the heterocycloalkyl that represents Y″ is chosen from:        piperidine, pyrrolidine and morpholine;    -   the arylalkyl and the aryl that represents Y″ are respectively        the benzyl radical and the phenyl radical;    -   the heteroaryl that represents Y″ is chosen from: pyridine,        pyrazine, furane and thiophene.

A more particular subject of the present invention is also a compound offormula I as defined above or a pharmaceutically acceptable salt of thelatter, and in which

-   -   the aryl that represents Z₃ is the phenyl or naphthyl radical;    -   the heteroaryl that represents Z₃ is chosen from        benzo[b]thiophene and benzo[b]furanne;    -   the heterocycloalkyl and the aryl that represents Y₃ are        respectively the pyrrolidine and p henyl radicals.

A more particular subject of the present invention is also a compound offormula I as defined above or a pharmaceutically acceptable salt of thelatter, and in which

-   -   the heterocycloalkyl that represents R″₄ is chosen from:        piperazine, piperidine, morpholine and pyrrolidine;    -   the aralkyl which optionally substitutes the heterocycloalkyl        that represents R″₄ is the benzyl radical;    -   the heteroaryl that represents R″₄ is imidazole;    -   the (C₃-C₇)cycloalkyl that represents Z₄ is cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;    -   the heteroaryl that represents Z₄ is chosen from: pyridine,        thiophene, indole and furane;    -   the aryl that represents Z₄ and is phenyl or naphthyl;    -   the aralkyl that represents Y₄ is benzyl;    -   the heterocycloalkyl that represents Y₄ is pyrrolidine;    -   the aralkyl which is substituted on the heterocycloalkyl that        form together W₄ and W′₄ is the benzyl radical.

Preferentially, a subject of the invention is a compound of formula I asdefined above or a pharmaceutically acceptable salt of the latter and inwhich A represents —C(O)— and R₁ and R₂ represent, independently, thehydrogen atom, a ((C₁-C₈)alkyl radical or a radical of formula—(CH₂)_(n)—X in which

-   -   X represents, amino, di(alkyl)amino, adamentyl, cyclohexyl,        cycloheptyl, piperidine, morpholine, pyrrolidine, phenyl,        pyridine, imidazole, thiophene, indole, carbazole being        optionally substituted (C₁-C₆)alkyl, or a radical of formula

-   -   the piperidine, pyrrolidine and phenyl radicals being optionally        substituted by one or more identical or different substituents        chosen from: —(CH₂)_(n′)—X′—Y′, halo, oxo, amino and        di((C₁-C₈)alkyl)amino;    -   X′ represents —O—, —S—, —C(O)—O—, —NH—C(O)—, —NH—SO₂— or a        covalent bond;    -   Y′ represents a (C₁-C₆)alkyl, oxazole, phenyl radical optionally        substituted by (C₁-C₄)alkyl or piperazine optionally substituted        by (C₁-C₄)alkyl;    -   or R₁ and R₂ form together, with the nitrogen atom to which they        are attached, piperidine, piperazine and diazepane,        thiazolidine, morpholine, or a cyclic radical of formula:

-   -   the radical that R₁ and R₂ form together being optionally        substituted by one or more identical or different substituents        chosen from:        -   —(CH₂)_(n″)—X″—Y″;        -   X″ represents —C(O)—, —C(O)—O— or a covalent bond;        -   Y″ represents a (C₁-C₆)alkyl; di(alkyl)amino, cyclopentyl,            cyclohexyl, piperidine, pyrrolidine, morpholine, benzyl,            pyridine, pyrazine, furane, thiophene, or phenyl radical            optionally substituted by one or more identical or different            substituents chosen from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,            (C₁-C₆)alkyl-carbonyl and halo; or Y″ represents a radical            of formula

Preferentially a subject of the invention is a compound of formula I asdefined above or a pharmaceutically acceptable salt of the latter and inwhich A represents —C(O)— and R₃ represents —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃

-   -   W₃ represents a covalent bond, —CH(OH)— or —C(O)—;    -   Z₃ represents a (C₁-C₆)alkyl, phenyl, naphthyl,        benzo[b]thiophene, benzo[b]furannyl radical, or a radical of        formula

-   -   the radical phenyl being optionally substituted by one or more        identical or different substituents chosen from:        —(CH₂)_(p″)—V₃—Y₃, halo, nitro, cyano;    -   V₃ represents —O—, —S—, —C(O)—, —C(O)—O—, —SO₂— or a covalent        bond;    -   Y₃ represents a (C₁-C₆)alkyl radical optionally substituted by        one or more identical or different halo; amino;        di((C₁-C₆)alkyl)amino; phenylcarbonylmethyl; pyrrolidine or        phenyl radicals;    -   p, p′ and p″ represent, independently, an integer from 0 to 2.

Preferentially a subject of the invention is a compound of formula I′ asdefined above or a pharmaceutically acceptable salt of the latter and inwhich A_(a) represents —C(O)— and the radicals R′₁, R′₂, R′₃ and R′₄have respectively the definitions of the R₁, R₂, R₃ and R₄ radicals asdefined above.

Preferentially a subject of the invention is a compound of formula I asdefined above or a pharmaceutically acceptable salt of the latter and inwhich A represents —C(O)— and R₄ represents a radical of formula—(CH₂)_(s)—R″₄

-   -   R″₄ represents the piperidine ring optionally substituted by        benzyl, piperazine optionally substituted by benzyl, or a        radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;    -   Q₄ represents a covalent bond, —CH₂—CH(OH)—, —CH₂—CH(OH)—CH₂—O—,        —CH₂—CH(OH)—CH₂—, —CH₂—CH(OH)—CH₂—O—CH₂— or —C(O)—O—;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally        substituted by (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,        (C₁-C₆)alkyldithio or one or two hydroxy; (C₂-C₆)alkenyl;        (C₂-C₆)alkynyl; cyclopropyl radicals optionally substituted by        alkoxycarbonyl; cyclobutyl, cyclopentyl optionally substituted        by hydroxyalkyl; cyclohexyl optionally substituted by one or        more alkyl; cycloheptyl, cyclohexene, adamantyl, pyridine,        thiophene, indole, furane, naphthyl; phenyl radicals optionally        substituted by one or more identical or different radicals        chosen from: —(CH₂)_(q″)—X₄—Y₄, hydroxy, halo and cyano;        -   X₄ represents —O— or a covalent bond;        -   Y₄ represents a (C₁-C₆)alkyl, di((C₁-C₆)alkyl)amino or            pyrrolidine radical.

Very preferentially a subject of the invention is also a compound offormula I as defined above in which A represents —C(O)—, Y represents—NH— and

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   R₃ represents —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃        -   W₃ represents a covalent bond; Z₃ represents the phenyl            radical substituted by one or more identical or different            substituents chosen from: —(CH₂)_(p″)—V₃—Y₃ and halo; V₃            represents —O— or —S—; and Y₃ represents a (C₁-C₆)alkyl            radical; p, p′ and p″ represent 0;    -   R₄ represents a radical of formula —(CH₂)_(s)—R″₄        -   R″₄ represents a radical of formula —NW₄W′₄        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;        -   Q₄ represents a covalent bond;        -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl optionally            substituted by hydroxy, (C₃-C₇)cycloalkyl, heteroaryl, aryl            optionally substituted by one or more identical or different            radicals chosen from formula —(CH₂)_(q″)—V₄—Y₄;        -   V₄ represents —O— or a covalent bond;        -   Y₄ represents a (C₁-C₆)alkyl or di((C₁-C₆)alkyl)amino            radical;        -   q″ represents 0; s represents an integer from 2 to 4, and s′            an integer from 1 to 2.            and very preferentially (C₃-C₇)cycloalkyl is chosen from            cyclopentyl and cyclohexyl, the heteroaryl represents            pyridine and the aryl represents phenyl; or a            pharmaceutically acceptable salt of the latter.

Preferentially, a subject of the invention is the invention is acompound of formula I′ as defined above or a pharmaceutically acceptablesalt of the latter and in which A_(a) represents —C(O)—, Y_(a)—NH—, theR′₁, R′₂ and R′₃ radicals have respectively the definitions of the R₁,R₂ and R₃ radicals as defined above, and R′₄ represents a radical offormula —(CH₂)_(s)—R″₄

-   -   R″₄ represents a radical of formula —NW₄W′₄    -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;    -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;    -   Q₄ represents a covalent bond;    -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl,        (C₃-C₇)cycloalkyl, heteroaryl, aryl optionally substituted by        one or more identical or different radicals chosen from formula        —(CH₂)_(q″)—V₄—Y₄;        -   V₄ represents —O— or a covalent bond;        -   Y₄ represents a (C₁-C₆)alkyl or di((C₁-C₆)alkyl)amino            radical;        -   q″ represents 0; s represents an integer from 2 to 4, and s′            an integer from 1 to 2.            and very preferentially the (C₃-C₇)cycloalkyl is chosen from            cyclopentyl and cyclohexyl, the heteroaryl represents            pyridine and the aryl phenyl; or a pharmaceutically            acceptable salt of the latter.

Very preferentially, a subject of the invention is also a compound offormula I as defined above in which A represents —C(O)—, Y representsthe sulphur atom and

-   -   R₁ and R₂ represent, independently, a (C₁-C₈)alkyl radical;    -   R₃ represents —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃        -   W₃ represents a covalent bond or —C(O)—; Z₃ represents the            phenyl radical substituted by one or more identical or            different substituents chosen from: —(CH₂)_(p″)—V₃—Y₃ and            halo; V₃ represents —O— or a covalent bond; and Y₃            represents a (C₁-C₆)alkyl or di((C₁-C₆)alkyl)amino radical;            p represents 1, and p′ and p″ represent 0;    -   R₄ represents a radical of formula —(CH₂)_(s)—R″₄        -   R″₄ represents a radical of formula —NW₄W′₄        -   W₄ represents the hydrogen atom or (C₁-C₈)alkyl;        -   W′₄ represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄;        -   Q₄ represents a covalent bond;            -   Z₄ represents the hydrogen atom, (C₁-C₈)alkyl,                heteroaryl, aryl    -   s represents an integer from 2 to 4, and s' an integer from 1 to        2,        and very preferentially the heteroaryl represents pyridine and        the aryl phenyl; or a pharmaceutically acceptable salt of the        latter.

Preferentially, a subject of the invention is a compound of formula I′as defined above or a pharmaceutically acceptable salt of the latter andin which A_(a) represents —C(O)—, Y_(a) a sulphur atom and the R′₁, R′₂,R′₃ and R′₄ radicals have respectively the definitions of the R₁, R₂, R₃and R₄ radicals as defined above when A represents —C(O)— and Y asulphur atom.

Preferentially, a subject of the invention is also a compound of formulaI as defined above in which A represents —CH₂—, Y—NH— and R₁ and R₂represent, independently, a ((C₁-C₆)alkyl radical; R₃ represents aphenyl substituted by one or more identical or different (C₁-C₆)alkoxysubstituents; R₄ represents a radical of formula —(CH₂), —R″₄; R″₄represents a radical of formula —NW₄W′₄; W₄ represents (C₁-C₈)alkyl; W′₄represents a radical of formula —(CH₂)_(s′)-Q₄-Z₄; Q₄ represents acovalent bond and Z₄ represents pyridine; or a pharmaceuticallyacceptable salt of the latter.

Preferentially, a subject of the invention is a compound of formula I′as defined above or a pharmaceutically acceptable salt of the latter andin which A_(a) represents —CH₂—, Y_(a)—NH— and the R′₁, R′₂, R′₃ and R′₄radicals have respectively the definitions of the R₁, R₂ R₃ and R₄radicals as defined above when A represents —CH₂— and Y—NH—.

In the present application, the symbol ->* corresponds to the point ofattachment of the radical. When the attachment site is not specified onthe radical, this means that the attachment is carried out on one of theavailable sites for such attachment of this radical.

According to the definitions of the variable groups A, Y, R₁, R₂, R₃ andR₄, the compounds according to the invention can be prepared in liquidphase according to the different procedures A to H described below.

A. Preparation According to Reaction Diagram A:

The compounds of formula I according to the invention in which Yrepresents —NH— and A represents —C(O)—, can be prepared according tothe following Diagram A:

As described in Diagram A, 4-fluoro-3-nitrobenzoic acid (1) can becoupled with a primary or secondary amine in the presence of a couplingagent such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, with orwithout 1-hydroxybenzotriazole (HOBt), in an inert organic solvent suchas methylene chloride, tetrahydrofuran or dimethylformamide at ambienttemperature for 3 to 24 hours in order to produce the correspondingamide (2). Treatment of the fluorinated derivative (2) with a primaryamine in the presence of an inorganic base such as cesium or potassiumcarbonate in an inert organic solvent such as dimethylformamide oracetonitrile at a temperature of 20-70° C. for 2 to 16 hours leads toderivative (3). The nitro function of the compound (3) is reduced bytreatment with tin chloride dihydrate in an inert solvent such as ethylacetate or dimethylformamide at a temperature of 60-80° C. for 3 to 15hours, or by catalytic hydrogenation in the presence of 10% palladium oncarbon in an inert solvent such as methanol, ethanol, ethyl acetate or amixture of these solvents, at a temperature of 18-25° C., for 2 to 8hours in order to produce dianiline (4). Derivative (4) is then treatedwith an isothiocyanate in the presence of a resin-supported or nonresin-supported coupling agent such as diisopropylcarbodiimide ordicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methylpolystyrene resin in an inert solvent such as tetrahydrofuran, methylenechloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hoursin order to produce derivative (5). Alternatively, derivative (4) can betreated with an isothiocyanate in an inert solvent such astetrahydrofuran, methylene chloride or chloroform then the resultingthiourea can be treated with methyl iodide in a polar solvent such asethanol for 3 to 24 hours at a temperature of 20-70° C. in order toproduce (5).

EXAMPLE A1N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamidehydrochloride

Stage 1: 4-fluoro-N,N-diisobutyl-3-nitrobenzamide

Diisopropylcarbodiimide (13.8 ml, 1.2 eq) is added to4-fluoro-3-nitrobenzoic acid (15 g, 1 eq) in solution in THF (150 ml).The mixture is stirred for 3 hours at a temperature of approximately 20°C. then diisobutylamine (12.9 ml, 1 eq) is added. After stirring for 15hours at approximately 20° C., the reaction mixture is evaporated underreduced pressure at 40° C. The residue is taken up in dichloromethane(200 ml) and water (70 ml). After decantation and extraction, thecombined organic phases are washed with salt water, followed by dryingover Na₂SO₄ then evaporating under reduced pressure at 40° C.Purification of the compound by flash chromatography on silica gel(eluent: heptane/ethyl acetate 8:2) produces the expected compound inthe form of a yellow solid (13.8 g; 63% yield).

MS/LC: MW calculated=296.3; m/z=297.2 (MH+)−Melting point=47° C.

Stage 2:N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzamide

A mixture of 4-fluoro-N,N-diisobutyl-3-nitrobenzamide (2.07 g, 1 eq),N-(2-pyridin-2-ylethyl)propane-1,3-diamine (1.6 g, 1.2 eq) and cesiumcarbonate (4.5 g, 2 eq) in acetonitrile (70 ml) is heated under refluxfor 3 hours then concentrated under reduced pressure at 40° C. Theresidue is taken up in dichloromethane (100 ml) and water (40 ml). Afterdecantation and extraction, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then evaporated under reduced pressure at40° C. Purification of the residue by flash chromatography on silica gel(eluent: dichloromethane 100 to dichloromethane/methanol 8:2) producesthe expected compound in the form of a yellow oil (3.1 g; 92% yield).

MS/LC: MW calculated=469.6; m/z=470.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ0.79 (m, 12H), 1.75 (m, 2H), 1.90 (m, 2H),2.23 (s, 3H), 2.48 (t, 3H, ³J=6 Hz), 2.71 (t, 2H, ³J=7 Hz), 2.87 (t, 2H,³J=7 Hz), 3.19 (d,4H, ³J=7 Hz), 3.33 (m, 2H), 7.01 (d, 1H), 7.10 (m,1H), 7.23 (d, 1H), 7.50 (m, 1H), 7.60 (m, 1H), 7.99 (s, 1H), 8.41 (m,1H), 8.59 (t, 1H, ³J=5 Hz).

Stage 3:3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzamide

N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzamide(2.9 g) in solution in an ethyl acetate/ethanol mixture (100 ml), and10% palladium on carbon (290 mg) are added together in an autoclave.After stirring for 7 hours under a hydrogen atmosphere (3 bars), thecatalyst is eliminated by filtration on Celite and the filtrate isconcentrated under reduced pressure at 40° C. in order to produce theexpected compound in the form of an oil (2.5 g, 92% yield).

MS/LC: MW calculated=439.6; m/z=440.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.77 (m, 12H), 1.71 (m, 2H), 1.90 (m, 2H),2.22 (s, 3H), 2.47 (m, 3H), 2.70 (t, 2H, ³J=7 Hz), 2.87 (t, 2H, ³J=7Hz), 3.0 (m, 2H), 3.17 (d, 4H, ³J=7.5 Hz), 4.62 (s, 2H), 4.71 (s, 1H),6.33 (d, 1H), 6.50 (d, 1H), 6.57 (s, 1H), 7.15 (m, 1H), 7.25 (d, 1H),7.63 (m, 1H), 8.45 (m, 1H).

Stage 4:N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamidehydrochloride

3,4,5 trimethoxyphenylisothiocyanate (27 mg, 1.2 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; load 1.69 mmol/g, 236 mg, 4 eq) are added successively to asolution of3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzamide(48 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated underreflux for 18 hours then cooled down to ambient temperature andaminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) isadded. After stirring for 4 hours at ambient temperature, the mixture isfiltered on frit and the filtrate is concentrated under reduced pressureat 40° C. The residue obtained is dissolved in ethyl ether and asolution of 1N HCl in ethyl ether is added dropwise in order to producethe expected compound in the form of the hydrochloride salt (80 mg, 89%yield).

MS/LC: MW calculated=630.8; m/z=631.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ0.66 (m, 6H), 0.91 (m, 6H), 1.71-2.03 (m,2H), 2.49 (m, 2H), 2.86 (s, 3H), 3.01-3.72 (m, 10H), 3.81 (s, 3H), 3.88(s, 6H), 4.58 (t, 2H, ³J=7 Hz), 6.93 (s, 2H), 7.30 (m, 2H), 7.60 (m,1H), 7.70 (m, 1H), 7.82 (d, 1H), 8.12 (m, 1H), 8.67 (d, 1H), 11.2 (s,1H), 11.7 (s, 1H), 13.0 (s, 1H).

EXAMPLE A21-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-dimethoxyphenyl)amino]-N,N-diisobutyl-1H-benzimidazole-5-carboxamidehydrochloride

Stage 1: 3-amino-4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-diisobutylbenzamide

Tin chloride dihydrate (3.58 g, 5eq) is added to a solution of4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-diisobutyl-3-nitrobenzamide(1.44 g, prepared according to the procedure described for Example A1),in ethyl acetate (40 ml). The mixture is heated under reflux for 7 hoursthen cooled down to a temperature of approximately 20° C. and pouredinto a saturated solution of NaHCO₃. After decanting and extracting withethyl acetate, the organic phases are combined, washed with salt water,dried over sodium sulphate and concentrated under reduced pressure at40° C. Purification by flash chromatography on silica gel (eluentdichloromethane/methanol 95:5) produces the compound in the form of afoam (1.06 g, 78% yield).

MS/LC: MW calculated=424.3; m/z=425.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.77 (m, 12H), 1.78 (m, 2H), 1.90 (m, 2H),2.12 (s, 3H), 2.49 (m, 3H), 3.06 (t, 2H, ³J=7 Hz), 3.17 (d, 4H, ³J=7.5Hz), 3.48 (s, 2H), 4.61 (s, 2H), 4.72 (s, 1H), 6.38 (d, 1H), 6.51 (m,1H), 6.59 (s, 1H), 7.19-7.30 (m, 5H).

Stage 2: 1-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-dimethoxyphenyl)amino]-N,N-diisobutyl-1H-benzimidazole-5-carboxamidehydrochloride

3,4 dimethoxyphenylisothiocyanate (35 mg, 1.2 eq) andN-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired fromNovabiochem; charge 1.69 mmol/g, 355 mg, 4 eq) are added successively toa solution of3-amino-4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-diisobutylbenzamide(65 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated underreflux for 18 hours then cooled down to ambient temperature andaminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) isadded. After stirring for 4 hours at ambient temperature, the mixture isfiltered on frit and the filtrate is concentrated under reduced pressureat 40° C. The residue obtained is dissolved in ethyl ether and a 1Nsolution of HCl in ethyl ether is added dropwise in order to produce theexpected compound in the form of the hydrochloride salt (81 mg, 92%yield).

MS/LC: MW calculated=585.3; m/z=586.5 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.85 (m, 6H), 0.92 (m, 6H), 1.85 (m, 1H),2.05 (m, 1H), 2.28 (m, 2H), 2.86 (s, 3H), 3.08-3.3 (m, 6H), 3.78 (s,6H), 4.20-4.40 (m, 2H), 4.50 (m, 2H), 6.42 (s, 1H), 6.90 (m, 2H), 7.22(m, 1H), 7.22-7.64 (m, 8H), 10.98 (m, 1H).

The following compounds were prepared according to reaction diagram Aand in a similar manner to the procedure described for the synthesis ofN,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamideor1-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-dimethoxyphenyl)amino]-N,N-diisobutyl-1H-benzimidazole-5-carboxamide:

In the above formula, R₁R₂N represents one of the radicals below:

R₃ represents one of the radicals below

and R₄ represents one of the radicals below (when R₄ represents aradical comprising a secondary amine termination, for examplepropylaminomethyl, the compounds were obtained by catalytichydrogenation in the presence of palladium on carbon of thecorresponding N-benzyl derivatives; and when R₄ represents a radicalcomprising a primary amine termination, for example ethylamino, thecompounds were obtained by acid treatment of the correspondingderivatives protected by a tertbutoxycarbonyl group).

B. Preparation According to Reaction Diagram B:

The compounds of formula I according to the invention in which Yrepresents —S— and A represents —C(O)—, can be prepared according to thefollowing Diagram B:

As described in Diagram B, the dianiline (4) can be treated withthiocarbonyldiimidazole (TCD) or thiophosgene in an inert organicsolvent such as tetrahydrofuran, methylene chloride or chloroform atambient temperature for 2 to 17 hours in order to produce derivative(6). Compound (6) is then alkylated by reaction with a halogenderivative such as an alkyl or benzyl iodide, bromide or chloride or abromoketone, in the presence of a tertiary base such as triethylamine ordiisopropylethylamine, or in the presence of a resin-supported tertiarybase such as morpholinomethyl polystyrene resin, in an inert organicsolvent such as tetrahydrofuran, choroform or methylene chloride, at atemperature of 20-70° C. for 3 to 24 hours. The resultingthiobenzimidazole (7) can be isolated, either by flash chromatography onsilica gel, or by adding to the reaction mixture a polymer-supportednucleophilic reagent such as for example an aminomethyl polystyreneresin, and a polymer-supported electrophilic reagent such as for example4-bromomethylphenoxymethyl polystyrene resin, followed by filtration andevaporation of the filtrate.

EXAMPLE B1N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide

Stage 1:N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

A mixture of3-amino-N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzamide(1.52 g, 1 eq) and thiocarbonyldiimidazole (0.74 g, 1.2 eq) in THF (30ml) is stirred at approximately 20° C. for 15 hours. After concentrationunder reduced pressure at 40° C., the residue obtained is taken up indichloromethane (80 ml) and water (30 ml). After decanting andextracting, the combined organic phases are washed with salt water,dried over Na₂SO₄ then evaporated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: 100% dichloromethane to dichloromethane/methanol 8:2) producesthe expected compound in the form of a light beige foam (1.2 g; 72%yield).

MS/LC: MW calculated=481.7; m/Z=482.3 (MH+)

NMR (1H, 400 MHz, DMSO-d₆): δ0.64 (m, 6H), 0.91 (m, 6H), 1.79-2.03 (m,4H), 2.18 (s, 3H), 2.37 (t, 3H, ³J=6.5 Hz), 2.66 (t, 2H, ³J=7 Hz), 2.83(t, 2H, ³J=7 Hz), 3.19 (m, 2H), 3.24 (m, 2H), 4.16 (t, 2H, ³J=7 Hz),7.05-7.65 (m, 6H), 8.43 (d, 1H), 12.79 (s, 1H).

Stage 2:N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide

Morpholinomethylpolystyrene resin (acquired from Novabiochem, 2 eq) and2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone are added successively to asolution ofN,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamidein tetrahydrofuran. The mixture is stirred for 15 hours at approximately20° C. then tetrahydrofuran, aminomethylpoystyrene resin (2 eq, acquiredfrom Novabiochem) and 4-bromomethylphenoxymethyl-polystyrene resin (3eq, acquired from Novabiochem) are added. After stirring for 6 hours,the mixture is filtered on frit. The filtrate is then concentrated todryness under reduced pressure at 40° C. in order to produce theexpected compound.

MS/LC: MW calculated=689.9; m/z=690.5 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ0.61 (m, 6H), 0.91 (m, 6H), 1.71-2.03 (m,4H), 2.19 (s, 3H), 2.35 (t, 3H, ³J=6.5 Hz), 2.67 (t, 2H, ³J=7 Hz), 2.85(t, 2H, ³J=7 Hz), 3.08-3.30 (m, 4H), 3.75 (s, 3H), 3.84 (s, 6H), 4.15(t, 2H, ³J=7 Hz), 5.09 (s, 2H), 7.11-7.67 (m, 8H), 8.45 (d, 1H).

The following compounds were prepared according to reaction diagram Band in a similar manner to the procedure described for the synthesis ofN,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide

In the above formula, R₁R₂N represents one of the radicals below:

R₃ represents one of the radicals below

and R₄ represents one of the radicals below

C. Preparation According to Reaction Diagram C:

The compounds of formula I according to the invention in which Yrepresents —NH— and A represents —C(O)—, can be prepared according tothe following Diagram C:

As described in Diagram C, 4-fluoro-3-nitrobenzoic acid can be convertedto methyl ester (8) by formation of a carboxylate salt using aninorganic base such as lithium hydroxide dihydrate or cesium carbonate,at ambient temperature for 30 minutes to 2 hours, in an inert organicsolvent such as tetrahydrofuran, followed by the addition ofdimethylsulphate at ambient temperature and stirring under reflux for 5to 15 hours. The fluorinated derivative (8) can be treated with aprimary amine in the presence of an inorganic base such as cesium orpotassium carbonate in an inert organic solvent such asdimethylformamide or acetonitrile at a temperature of 20-70° C. for 2 to16 hours in order to produce derivative (9). The nitro function ofcompound (9) is reduced by treatment with tin chloride dihydrate in aninert solvent such as ethyl acetate or dimethylformamide, at atemperature of 60-80° C. for 3 to 15 hours, or by catalytichydrogenation in the presence of 10% palladium on carbon in an inertsolvent such as methanol, ethanol, ethyl acetate or a mixture of thesesolvents, at a temperature of 18-25° C., for 2 to 8 hours, in order toproduce dianiline (10). Derivative (10) is then treated with anisothiocyanate in the presence of a coupling agent such asdiisopropylcarbodiimide or dicyclohexylcarbodiimide in an inert solventsuch as tetrahydrofuran, methylene chloride or chloroform at atemperature of 20-70° C. for 2 to 72 hours in order to producederivative (11). Alternatively, derivative (10) can be treated with anisothiocyanate in an inert solvent such as tetrahydrofuran, methylenechloride or chloroform, then the resulting thiourea can be treated withmethyl iodide in a polar solvent such as ethanol for 3 to 24 hours at atemperature of 20-70° C. in order to produce (11). The methyl ester (11)can then be saponified in the presence of an inorganic base such aslithium hydroxide dihydrate in a mixture of polar solvents such as waterand tetrahydrofuran at a temperature of 20 to 70° C. for 3 to 17 hours.The resulting acid (12) can be coupled with a primary or secondary aminein the presence of a coupling agent such as diisopropylcarbodiimide,dicyclohexylcarbodiimide or carbonyldiimidazole, with or without1-hydroxybenzotriazole (HOBt) in an inert organic solvent such asmethylene chloride, tetrahydrofuran or dimethylformamide at ambienttemperature for 3 to 24 hours. The corresponding amide (13) can beisolated, either by flash chromatography on silica gel, or by adding tothe reaction mixture a polymer-supported nucleophilic reagent such asfor example an aminomethyl polystyrene resin and a polymer-supportedelectrophilic reagent such as for example methylisothiocyanatepolystyrene resin, followed by filtration and evaporation of thefiltrate.

EXAMPLE C11-(2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazol-5-yl)-3-thien-2-ylpropan-1-one

Stage 1: methyl 4-fluoro-3-nitrobenzoate

Lithium hydroxide monohydrate (4.5 g, 1 eq) is added in small portionsto a solution of 4-fluoro-3-nitrobenzoic acid (20 g, 1 eq) intetrahydrofuran (100 ml). After stirring for 1 hour at approximately 20°C., dimethylsulphate (10.2 ml) is added dropwise to the yellowprecipitate. The reaction mixture is then heated under reflux for 8hours then concentrated under reduced pressure at 40° C. The residue isdiluted in dichloromethane and Na₂C₀₋₃ saturated water. After decantingand extracting, the combined organic phases are washed with salt water,dried over sodium sulphate and concentrated under reduced pressure at40° C. The yellow solid obtained is recrystallized from a diethylether/petroleum ether mixture in order to produce the expected compoundin the form of a light yellow powder (16.7 g, 78% yield). Meltingpoint=59° C.

NMR (¹H, 400 MHz, DMSO-d₆): δ3.99 (s, 3H), 7.39 (m, 1H), 8.33 (s, 1H),8.74 (s, 1H).

Stage 2: methyl4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitro benzoate

A mixture of methyl 4-fluoro-3-nitrobenzoate (5.08 g, 1 eq), ofN-(2-pyridin-2-ylethyl)propane-1,3-diamine (5.4 g, 1.2 eq) and potassiumcarbonate (7.0 g, 2 eq) in acetonitrile (180 ml) is heated under refluxfor 3 hours then concentrated under reduced pressure at 40° C. Theresidue is taken up in dichloromethane (150 ml) and water (60 ml). Afterdecanting and extracting, the combined organic phases are washed withsalt water, dried over Na₂SO₄ then evaporated under reduced pressure at40° C. Purification of the compound by flash chromatography on silicagel (eluent: dichloromethane to dichloromethane/methanol 9:1) producesthe expected compound in the form of an orange-coloured oil (9.2 g; 97%yield).

MS/LC: MW calculated=372.4; m/z=373.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ1.75 (m, 2H), 2.23 (s, 3H), 2.48 (t, 3H,³J=6 Hz), 2.71 (t, 2H, ³J=7.8 Hz), 2.86 (t, 2H, ³J=7.8 Hz), 3.35 (m,2H), 3.81 (s, 3H), 7.05 (d, 1H), 7.10 (m, 1H), 7.23 (d, 1H), 7.59 (m,1H), 7.93 (m, 1H), 8.40 (d, 1H), 8.59 (s, 1H), 8.87 (t, 1H, ³J=5 Hz).

Stage 3: methyl3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate

Methyl4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzoate(9.1 g) in solution in an ethyl acetate/methanol mixture and 10%palladium on carbon (910 mg) are added together in an autoclave. Afterstirring for 4 hours under a hydrogen atmosphere (3 bars), the catalystis eliminated by filtration on Celite and the filtrate is concentratedunder reduced pressure at 40° C. in order to produce the expectedcompound in the form of an oil (8.2 g, 98% yield).

MS/LC: MW calculated=342.4; m/z=343.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.71 (m, 2H), 2.21 (s, 3H), 2.46 (t, 3H,³J=6.8 Hz), 2.68 (t, 2H, ³J=7 Hz), 2.86 (t, 2H, ³J=7 Hz), 3.05 (m, 2H),3.71 (s, 3H), 4.70 (s, 2H), 5.23 (t, 1H, ³J=7 Hz), 6.37 (d, 1H),7.14-7.26 (m, 4H), 7.64 (m, 1H), 8.45 (m, 1H).

Stage 4:methyl-2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate

3,5 dimethoxyphenylisothiocyanate (571 mg, 1 eq) anddiisopropylcarbodiimide (1.35 ml, 4 eq) are added successively to asolution of methyl3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate(1.0 g, 1 eq) in tetrahydrofuran (10 ml). The mixture is heated underreflux for 18 hours then cooled down to ambient temperature andconcentrated under reduced pressure at 40° C. The residue is taken up inethyl acetate (100 ml) and water (40 ml). After decanting andextracting, the combined organic phases are washed with salt water,dried over Na₂SO₄ then evaporated under reduced pressure at 40° C.Purification of the residue by flash chromatography on silica gel(eluent: dichloromethane/methanol 99:1 to 98:2) produces the expectedcompound in the form of a beige foam (1.12 g; 76% yield).

MS/LC: MW calculated=503.6 m/z=504.3 (MH+)

NMR (¹H, 400 MHz, CDCl₃): δ 2.08 (m, 2H), 2.40 (t, 2H, ³J=7 Hz), 2.45(s, 3H), 2.99 (t, 2H, ³J=7 Hz), 3.09 (t, 2H, ³J=7 Hz), 3.82 (s, 6H),3.93 (s, 3H), 4.01 (t, 2H, ³J=6 Hz), 6.15 (m, 1H), 6.92-7.54 (m, 6H),7.87 (m, 1H), 8.25 (s, 1H), 8.51 (m, 1H), 9.37 (s, 1H).

Stage 5:2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylicacid

Lithium hydroxide (0.350 g, 4 eq) is added to a solution ofmethyl-2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate(1.05 g, 1 eq) in a mixture of tetrahydrofuran (10 ml) and water (5 ml).The mixture is stirred at 65° C. for 18 hours then cooled down toambient temperature and concentrated under reduced pressure at 40° C.Ethyl acetate and water are added to the residue. The mixture isacidified by adding acetic acid to pH 5. After decanting and extracting,the combined organic phases are dried over sodium sulphate andconcentrated under reduced pressure. Purification by flashchromatography on silica gel (eluent: dichloromethane/ethanol 95/5 to70/30) produces the expected compound in the form of a white foam (0.93g, 91% yield).

MS/LC: MW calculated=489.6; m/z=490.1 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.88 (m, 2H), 2.23 (s, 3H), 2.31 (t, 2H,³J=6.5 Hz), 2.74 (t, 2H, ³J=7 Hz), 2.91 (t, 2H, ³J=7 Hz), 3.72 (s, 6H),4.14 (t, 2H, ³J=6.5 Hz), 6.14 (m, 1H), 7.09-7.72 (m, 8H), 7.93 (s, 1H),8.44 (m, 1H), 9.21 (s, 1H).

Stage 6:1-(2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazol-5-yl)-3-thien-2-ylpropan-1-one

Carbonyldiimidazole (10.5 mg, 1.3 eq) in solution in chloroform (0.2 ml)is added to a solution of2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylicacid (24 mg, 1 eq) in a mixture of dimethylformamide (0.2 ml) andtetrahydrofuran (0.4 ml). The mixture is stirred for 15 hours atapproximately 20° C. then thiophene-2-ethylamine (13 mg, 2 eq) insolution in tetrahydrofuran (0.1 ml) is added. After stirring for 15hours at approximately 20° C., aminomethyl polystyrene resin (2 eq),TBD-methyl polystyrene resin (2 eq) and methylisothiocyanate polystyreneresin (4 eq) are added to the mixture diluted in dichloromethane. Afterstirring for 6 hours at approximately 20° C., the mixture is filteredand the filtrate is concentrated under reduced pressure at 40° C. inorder to produce the expected compound in the form of an oil (27 mg, 90%yield).

MS/LC: MW calculated=598.8; m/z=599.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.87 (m, 2H), 2.26 (s, 3H), 2.48 (t, 2H,³J=6.5 Hz), 2.78 (m, 2H), 2.93 (t, 2H, ³J=7 Hz), 3.08 (t, 2H, ³J=7 Hz),3.50 (m, 2H), 3.72 (s, 6H), 4.14 (t, 2H, ³J=6.5 Hz), 6.14 (m, 1H),6.92-7.93 (m, 12H), 8.45 (m, 1H), 9.16 (s, 1H).

The following compounds were prepared according to reaction diagram Cand in a similar manner to the procedure described for the synthesis of1-(2-[(3,5-dimethoxyphenyl)amino]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazol-5-yl)-3-thien-2-ylpropan-1-one:

In the above formula, R₁R₂N represents one of the radicals below:

R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

D. Preparation According to Reaction Diagram D:

The compounds of formula I according to the invention in which Yrepresents —S— and A represents —C(O)—, can be prepared according to thefollowing Diagram D:

As described in Diagram D, dianiline (10) can be treated withthiocarbonyldiimidazole (TCD) or thiophosgene in an inert organicsolvent such as tetrahydrofuran, at ambient temperature for 2 to 17hours in order to produce derivative (14). Compound (14) is thenalkylated by reacting with a halogenated derivative such as an alkyl orbenzyl iodide, bromide or chloride or a bromoketone, in the presence ofa tertiary base such as triethylamine or diisopropylethylamine, in aninert organic solvent such as tetrahydrofuran, choroform or methylenechloride, at a temperature of 20-70° C. for 3 to 24 hours in order toproduce the thiobenzimidazole derivative (15). The methyl ester (15) canthen be saponified in the presence of an inorganic base such as lithiumhydroxide monohydrate in a mixture of polar solvents such as water andtetrahydrofuran at a temperature of 20 to 70° C. for 3 to 17 hours. Theresulting acid (16) can be coupled with a primary or secondary amine inthe presence of a coupling agent such as diisopropylcarbodiimide,dicyclohexylcarbodiimide or carbonyldiimidazole, with or without1-hydroxybenzotriazole (HOBt) in an inert organic solvent such asmethylene chloride, tetrahydrofuran or dimethylformamide at ambienttemperature for 3 to 24 hours. The corresponding amide (17) can beisolated, either by flash chromatography on silica gel, or by adding apolymer-supported nucleophilic reagent such as for example anaminomethyl polystyrene resin and a polymer-supported electrophilicreagent such as for example methylisothiocyanate polystyrene resin tothe reaction mixture, followed by filtration and evaporation of thefiltrate.

EXAMPLE D13-(2-[(3-bromobenzyl)sulphanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazol-1-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine

Stage 1: methyl1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxylate

A mixture of methyl3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate(4.09 g, 1 eq) and thiocarbonyldiimidazole (2.77 g, 1.3 eq) intetrahydrofuran (100 ml) is stirred at approximately 20° C. for 15hours. After concentration under reduced pressure at 40° C., the residueobtained is taken up in dichloromethane (150 ml) and water (50 ml).After decanting and extracting, the combined organic phases are washedwith salt water, dried over Na₂SO₄ then evaporated under reducedpressure at 40° C. Purification by flash chromatography on silica gel(eluent: 100% dichloromethane to dichloromethane/methanol 9:1) producesthe expected compound in the form of a foam (3.94 g; 85% yield).

MS/LC: MW calculated 384.5; m/z=385.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.86 (m, 2H), 2.18 (s, 3H), 2.37 (t, 3H,³J=6.8 Hz), 2.65 (t, 2H, ³J=7 Hz), 2.84 (t, 2H, ³J=7 Hz), 3.85 (s, 3H),4.16 (t, 2H, ³J=7 Hz), 7.16-7.81 (m, 6H), 8.44 (m, 1H), 12.95 (s, 1H).

Stage 2: methyl2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate

Triethylamine (0.82 ml, 1.6 eq) and 3-bromobenzylbromide (0.97 g, 1 eq)are added successively to a solution of methyl1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxylate(1.5 g) in tetrahydrofuran (30 ml). The mixture is stirred for 15 hoursat approximately 20° C. then concentrated under reduced pressure at 40°C. The residue obtained is diluted in ethyl acetate and water. Afterdecanting and extracting, the organic phases are washed with salt water,dried over sodium sulphate and concentrated under reduced pressure at40° C. Purification by flash chromatography on silica gel (eluent:dichloromethane/methanol 95/5 to 90/10) produces the expected compoundin the form of a colourless oil (1.5 g; 70% yield).

MS/LC: MW calculated=553.5; m/z=553.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 1.76 (m, 2H), 2.14 (s, 3H), 2.27 (t, 3H,³J=6.5 Hz), 2.62 (t, 2H, ³J=7 Hz), 2.81 (t, 2H, ³J=7 Hz), 3.86 (s, 3H),4.06 (t, 2H, ³J=7 Hz), 4.61 (s, 2H), 7.15-7.82 (m, 9H), 8.13 (s, 1H),8.43 (d, 1H).

Stage 3:2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylicacid

Lithium hydroxide (0.315 g, 3 eq) is added to a solution of methyl2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylate(1.03 g, 1 eq) in a mixture of tetrahydrofuran (10 ml) and water (5 ml).The mixture is heated under reflux for 18 hours then cooled down toambient temperature and concentrated under reduced pressure at 40° C.Ethyl acetate and water are added to the residue. The mixture isacidified by adding acetic acid to pH 5. After decanting and extracting,the combined organic phases are dried over sodium sulphate andconcentrated under reduced pressure. Purification by flashchromatography on silica gel (eluent: dichloromethane/methanol 95/5 to80/20) produces the expected compound in the form of a foam (0.85 g, 85%yield).

MS/LC: MW calculated=539.5; m/z=539.2 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ1.76 (m, 2H), 2.14 (s, 3H), 2.29 (t, 3H,³J=6.5 Hz), 2.62 (t, 2H, ³J=7 Hz), 2.82 (t, 2H, ³J=7 Hz), 4.04 (t, 2H,³J=7 Hz), 4.61 (s, 2H), 7.15-7.82 (m, 9H), 8.10 (s, 1H), 8.43 (d, 1H).

Stage 4:3-(2-[(3-bromobenzyl)sulphanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazol-1-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine

Carbonyldiimidazole (10.5 mg, 1.3 eq) in solution in chloroform (0.2 ml)is added to a solution of2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylicacid (27 mg, 1 eq) in a mixture of dimethylformamide (0.2 ml) andtetrahydrofuran (0.4 ml). The mixture is stirred for 15 hours atapproximately 20° C. then 4-(1-pyrrolidinyl)piperidine (15 mg, 2 eq) isadded. After stirring for 15 hours at approximately 20° C., aminomethylpolystyrene resin (2 eq, acquired from Novabiochem), TBD-methylpolystyrene resin (2 eq, acquired from Novabiochem) andmethylisothiocyanate polystyrene resin (4 eq, acquired from Novabiochem)are added to the mixture diluted in dichloromethane. After stirring for6 hours at approximately 20° C., the mixture is filtered and thefiltrate is concentrated under reduced pressure at 40° C. in order toproduce the expected compound in the form of an oil (28 mg, 84% yield).

MS/LC: MW calculated=675.7; m/z=674.2 (MH+)

NMR (¹H, 400 MHz, CDCl₃): δ 1.4-1.98 (m, 10H), 2.26 (s, 3H), 2.32 (m,5H), 2.60-3.15 (m, 8H), 3.81 (m, 1H), 4.01 (t, 2H, ³J=7 Hz), 4.50 (m,1H), 4.57 (s, 2H), 7.08-7.72 (m, 10H), 8.51 (d, 1H).

The following compounds were prepared according to reaction Diagram Dand in a similar manner to the procedure described for the synthesis of3-(2-[(3-bromobenzyl)sulphanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazol-1-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine:

In the above formula, R₁R₂N represents one of the radicals below:

R₃ represents one of the radicals below:

and R₄ represents one of the radicals below:

E. Preparation According to Reaction Diagram E:

The compounds of formula I according to the invention in which Arepresents —(CH₂)— can be prepared from compounds in which A represents—C(O)—, according to the following Diagram E:

As described in Diagram E, the amide (18) prepared according to reactiondiagrams A or B, can be reduced to the corresponding amine (19) usingborane or lithium aluminium hydride in an aprotic solvent such astetrahydrofuran or diethyl ether at a temperature of 0 to 70° C., for 1to 6 hours.

EXAMPLE E15-[(diisobutylamino)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethyl]amino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine

A molar solution of lithium aluminium hydride in tetrahydrofuran (0.83ml, 5 eq) is added dropwise to a solution ofN,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide(105 mg, 1 eq. prepared according to Example A1) cooled down to 0° C.,in tetrahydrofuran (3 ml). After stirring for 15 minutes at 0° C., themixture is heated at 60° C. for 3 hours then cooled down to 0° C. andhydrolysed. After adding ethyl acetate, decanting and extraction, thecombined organic phases are washed with salt water, followed by dryingover sodium sulphate and concentrating under reduced pressure.Purification by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 9:1) produces the expectedcompound in the form of a foam (63 mg, 62% yield).

MS/LC: MW calculated=616.8; m/z=617.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.81 (d, 12H), 1.77 (m, 2H), 1.86 (m, 2H),2.06 (d, 4H), 2.24 (s, 3H), 2.49 (t, 2H, ³J=6 Hz), 2.74 (t, 2H, ³J=7Hz), 2.91 (t, 2H, ³J=7 Hz), 3.48 (s, 2H), 3.62 (s, 3H), 3.78 (s, 6H),4.05 (m, 2H), 6.97 (d, 1H), 7.13-7.24 (m, 5H), 7.63 (m, 1H), 8.43 (d,1H), 8.94 (s, 1H).

F. Preparation According to Reaction Diagram F:

The compounds of formula I according to the invention in which Yrepresents —S— and —NH— and A represents —CH₂—, can be preparedaccording to the following Diagram F:

As described in Diagram F, derivative (3) can be reduced to compound(20) using borane in an aprotic solvent such as tetrahydrofuran ordiethyl ether at a temperature of 0 to 70° C., for 18 to 24 hours. Thedianiline (20) can be then treated with an isothiocyanate in thepresence of a resin-supported or non-resin-supported coupling agent suchas diisopropylcarbodiimide or dicyclohexylcarbodiimide orN-methylcyclohexylcarbodiimide N-methyl polystyrene resin in an inertsolvent such as tetrahydrofuran, methylene chloride, or chloroform at atemperature of 20-70° C. for 2 to 72 hours in order to producederivative (21). Alternatively, derivative (4) can be treated with anisothiocyanate in an inert solvent such as tetrahydrofuran, methylenechloride or chloroform, then the resulting thiourea can be treated withmethyl iodide in a polar solvent such as ethanol for 3 to 24 hours at atemperature of 20-70° C. in order to produce (21).

As also described in reaction diagram B and Example B1, the dianiline(20) can be treated with thiocarbonyldiimidazole (TCD) or thiophosgenein an inert organic solvent such as tetrahydrofuran, methylene chlorideor chloroform at ambient temperature for 2 to 17 hours in order toproduce derivative (22). Compound (22) is then alkylated by reactingwith a halogenated derivative such as an alkyl or benzyl iodide, bromideor chloride or a bromoketone, in the presence of a tertiary base such astriethylamine or diisopropylethylamine, or in the presence of aresin-supported tertiary base such as morpholinomethyl polystyreneresin, in an inert organic solvent such as tetrahydrofuran, choroform ormethylene chloride, at a temperature of 20-70° C. for 3 to 24 hours. Theresulting thiobenzimidazole derivative (23) can be isolated, either byflash chromatography on silica gel, or by adding a polymer-supportednucleophilic reagent such as for example an aminomethyl polystyreneresin, and a polymer-supported electrophilic reagent such as for example4-bromomethylphenoxymethyl polystyrene resin to the reaction mixture,followed by filtration and evaporation of the filtrate.

EXAMPLE F1 5-[(diisobutylamino)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethylamino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine

Stage 1:4-[(diisobutylamino)methyl]-N-(3-{methyl[2-(4-pyridinyl)ethyl]amino}propyl)-1,2-benzenediamine

A molar solution of borane-tetrahydrofuran complex (6.25 ml, 15 eq) isadded dropwise to a solution ofN,N-diisobutyl-4-({3-[methyl(2-pyridin-4-ylethyl)amino]propyl}amino)-3-nitrobenzamide(200 mg, 1 eq) in tetrahydrofuran (3 ml) cooled down to 0° C. Themixture is heated under reflux for 20 hours then cooled down to 0° C.and hydrolysed with a 6N aqueous solution of hydrochloric acid (12 ml).After 1 hour 30 minutes under reflux, the mixture is cooled down to 0°C. and brought to basic pH by a 6N aqueous solution of soda. Afteradding ethyl acetate, decanting and extracting, the organic phases arecombined, followed by washing with salt water, drying over sodiumsulphate and evaporating under reduced pressure. Purification by flashchromatography on silica gel (eluent: 100% dichloromethane todichloromethane/methanol 8:2) produces the expected compound in the formof an oil (92 mg, 51% yield).

MS/LC: MW calculated=425.6; m/z=426.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.83 (d, 12H), 1.72 (m, 4H), 2.03 (d, 4H,³J=7 Hz), 2.23 (s, 3H), 2.48 (t, 2H, ³J=7 Hz), 2.60 (t, 2H, ³J=7 Hz),2.75 (t, 2H, ³J=7 Hz), 2.96 (m, 2H), 3.38 (s, 2H), 4.30 (m, 3H), 6.30(d, 1H), 6.42 (d, 1H), 6.51 (s, 1H), 7.25 (d, 1H), 7.45 (m, 1H), 8.41(m, 2H).

Stage 2:5-[(diisobutylamino)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethyl]amino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine

3,4,5 trimethoxyphenylisothiocyanate (57 mg, 1.2 eq) andN-methylcyclohexylcarbodiimide-N-methyl polystyrene resin (acquired fromNovabiochem; load 1.69 mmol/g, 501 mg, 4 eq) are added successively to asolution of4-[(diisobutylamino)methyl]-N-(3-{methyl[2-(4-pyridinyl)ethyl]amino}propyl)-1,2-benzenediamine(90 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated underreflux for 18 hours then cooled down to ambient temperature andaminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) isadded. After stirring for 4 hours at ambient temperature, the mixture isfiltered on frit and the filtrate is concentrated under reduced pressureat 40° C. Purification by flash chromatography on silica gel (eluent:100% dichloromethane to dichloromethane/methanol 9:1) produces theexpected compound in the form of a beige foam (92 mg, 83% yield).

MS/LC: MW calculated=616.8; m/z=617.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ0.81 (d, 12H), 1.77 (m, 2H), 1.86 (m, 2H),2.06 (d, 4H), 2.22 (s, 3H), 2.31 (t, 2H, ³J=6 Hz), 2.55 (t, 2H, ³J=7Hz), 2.71 (t, 2H, ³J=7 Hz), 3.49 (s, 2H), 3.68 (s, 3H), 3.77 (s, 6H),4.11 (m, 2H), 6.99 (d, 1H), 7.13-7.25 (m, 6H), 8.39 (d, 2H), 8.90 (s,1H).

G. Preparation According to Reaction Diagram G:

The compounds of formula I according to the invention in which Arepresents —C(O)— and R₄ represents —NW₄W′₄, can be prepared accordingto the following Diagram G:

As described in Diagram G, the benzimidazole derivative (24), preparedaccording to reaction diagrams A, B, C or D can be treated with anorganic or inorganic acid such as trifluoroacetic acid or hydrogenchloride (aqueous or gaseous form) in an aprotic solvent such asdichloromethane or ethyl acetate at a temperature of 0-20° C. for 0.5 to5 hours, in order to produce the amine (25). The amine (25) can then betreated with an epoxide in a protic or aprotic polar solvent such asmethanol, ethanol or acetonitrile, in the presence or not of lithiumperchlorate or ytterbium triflate, at a temperature of 20-80° C. for 4to 48 hours in order to produce compound (26). The amine (25) can alsoreact with an aldehyde in a protic or aprotic solvent, such asdichloromethane, tetrahydrofuran or methanol, for 1 to 15 hours at atemperature of 0-50° C. The resulting imine is then reduced in situ by aresin-supported or non resin-supported reducing agent, preferablyresin-supported sodium triacetoxyborohydride, sodium cyanoborohydride orborohydride, with or without the presence of an acid such as aceticacid, at a temperature of 20 to 50° C. for a duration of 0.2 to 5 hours,in order to produce compound (27).

The compounds 27 for which s=3 can also be prepared according to thefollowing Diagram G′:

Such as described in Diagram G′, the derivative (30) prepared accordingto reaction Diagrams A, B, C or D can be treated either with an organicacid such as pyridinium tosylate or paratoluenesulphonic acid in anaprotic solvent such as acetone in the presence of water, at atemperature of 20-70° C. for 2 to 12 hours, or with an inorganic acidsuch as aqueous hydrogen chloride in an aprotic solvent such astetrahydrofuran at a temperature of 0-20° C. for 6 to 18 hours in orderto produce compound (31). The aldehyde (31) can then be treated with anamine in a protic or aprotic solvent such as dichloromethane,tetrahydrofuran or methanol for 1 to 18 hours at a temperature of 20° C.The resulting imine is then reduced in situ by a reducing agent,preferably sodium triacetoxyborohydride or sodium cyanoborohydride, inthe presence or not of an acid such as acetic acid, at a temperature of20-50° C. for a duration of 0.2 to 6 hours, in order to produce compound(27′).

EXAMPLE G11-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

Stage 1: 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide hydrochloride

A stream of dry HCl is passed through a solution of tert-butyl2-{5-[(diisobutylamino)carbonyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazol-1-yl}ethylcarbamate (2.56 g, preparedaccording to the procedure described in Example A1, reaction diagram A)in ethyl acetate (100 ml), (100% ethyl acetate) cooled down to 0° C.until the TLC shows complete disappearance of the starting product. Theresulting mixture is then evaporated under reduced pressure. The solidobtained is triturated in diethylether and filtered in order to producethe expected compound in the form of white crystals (2.25 g, 97% yield).

MS/LC: MW calculated=497.6; m/z=498.3 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.67 (m, 6H), 0.92 (m, 6H), 1.84-2.03 (m,2H), 3.10-3.17 (m, 4H), 3.38 (m, 2H), 3.71 (s, 3H), 3.81 (s, 6H), 4.76(m, 2H), 6.93 (s, 2H), 7.30 (m, 2H), 7.81 (d, 1H), 8.56 (m, 3H).

Stage 2:1-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

A solution of1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide(30 mg, 1 eq) and cyclohexanecarboxaldehyde (5 mg, 0.8 eq) in methanol(0.7 ml) is stirred at a temperature of approximately 20° C. for 4hours. Borohydride resin (48 mg, 2.5 mmol/g, Amberlite (, IRA-400) isadded and the mixture is stirred for 18 hours then dichloromethane (0.5ml) and benzyloxybenzaldehyde Wang resin (37 mg, 3.22 mmol/g,Novabiochem) are added. After stirring overnight, the mixture isfiltered and the filtrate is evaporated under reduced pressure in orderto produce the expected compound in the form of a beige foam (18 mg,65%).

MS/LC: MW calculated=593.8; m/z=594.4 (MH+)

NMR (¹H, 400 MHz, CDCl₃): δ 0.65-1.80 (m, 23H), 2.60 (d, 2H), 3.13 (m,2H), 3.82 (s, 3H), 3.90 (s, 6H), 4.10 (m, 2H), 6.91 (s, 2H), 7.07; 7.16(AB, 2H), 7.53 (s, 1H), 10.1 (s, 1H).

The following compounds were prepared according to reaction Diagram Gand in a similar manner to the procedure described for the synthesis of1-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide(a final purification by flash chromatography on silica gel can also becarried out):

In the above formula, R₄ represents one of the radicals below:

EXAMPLE G21-{2-[(1-hydroxy-2-phenylethyl)amino]ethyl}-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

Lithium perchlorate (16 mg, 3 eq) then after 5 minutes1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (25 mg, 1 eq) are added, ata temperature of approximately 20° C. to a solution of2,3-epoxypropylbenzene (7 mg, 1 eq) in acetonitrile (0.5 ml). Themixture is heated under reflux for 24 hours then cooled down to ambienttemperature and hydrogen carbonate and dichloromethane saturated wateris added. After decanting and extracting, the organic phases arecombined and washed with salt water, followed by drying over sodiumsulphate and evaporating under reduced pressure at 40° C. Purificationof the oil obtained by flash chromatography on silica gel (100%dichloromethane to dichloromethane/methanol 80:20) produces the expectedcompound in the form of an oil (31 mg, 55% yield)

MS/LC: MW calculated=631.8; m/z=632.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ 0.83 (m, 6H), 0.91 (m, 6H), 1.81-2.10 (m,2H), 2.57-2.65 (m, 3H), 2.91 (m, 2H), 3.21 (m, 4H), 3.62 (s, 3H), 3.75(m, 7H), 4.22 (m, 2H), 4.74 (d, 1H), 6.97-7.33 (m, 10H).

The following compounds were prepared according to reaction diagram Gand in a similar manner to the procedure described for the synthesis of1-{2-[(1-hydroxy-2-phenylethyl)amino]ethyl}-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide:

In the above formula, R₄ represents one of the radicals below:

H. Preparation According to Reaction Diagram H:

The compounds of formula I according to the invention in which Arepresents —C(O)—, Y represents —S— and R₃ represents—(CH₂)_(p)—CH(OH)—(CH₂)_(p′)-Z₃, can be prepared according to thefollowing diagram H:

As described in Diagram H, the thiobenzimidazole derivative (28),prepared according to reaction diagrams B or D, can be treated with areducing agent such as sodium borohydride in a protic solvent such asmethanol at a temperature of 0-20° C. for 0.2 hours to 1 hour, in orderto produce the corresponding alcohol (29).

EXAMPLE H12-{[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxamide

Sodium borohydride (8 mg, 2 eq) is added at 0° C. to a solution ofN,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide(69 mg, 1 eq) in methanol (2 ml). After stirring for 10 minutes at 0°C., the mixture is taken to a temperature of approximately 20° C. andstirred at this temperature for 30 minutes. The mixture is thenconcentrated under reduced pressure at 40° C. then water saturated withammonium chloride and dichloromethane is added. After decanting andextracting, the organic phases are combined and washed with salt water,dried over sodium sulphate and evaporated under reduced pressure at 40°C. Purification of the oil obtained by flash chromatography on silicagel (100% dichloromethane to dichloromethane/methanol 80:20) producesthe expected compound in the form of an oil (61 mg, 88% yield).

MS/LC: MW calculated=691.9; m/z=692.4 (MH+)

NMR (¹H, 400 MHz, DMSO-d₆): δ0.61 (m, 6H), 0.91 (m, 6H), 1.71-2.03 (m,4H), 2.17 (s, 3H), 2.31 (t, 3H, ³J=6.5 Hz), 2.65 (t, 2H, ³J=7 Hz), 2.85(t, 2H, ³J=7 Hz), 3.08-3.30 (m, 4H), 3.56 (m, 1H), 3.60 (s, 3H), 3.71(m, 1H), 3.75 (s, 6H), 4.05 (t, 2H, ³J=7 Hz), 4.86 (m, 1H), 5.87 (d,1H), 6.75 (s, 2H), 7.11-7.65 (m, 6H), 8.43 (d, 1H).

Preparation of the Synthesis Reagents

N-(2-pyridin-2-yl ethyl)propane-1,3-diamine

Acrylonitrile (10.1 ml, 1.1 eq) is added slowly to a solution cooleddown to approximately 4° C. of 2-[2-(methylamino)ethyl]pyridine (19.5ml, 1 eq) in methanol (200 ml). The reaction medium is then stirred for3 hours at approximately 20° C. then concentrated under reduced pressureat 40° C. in order to produce3-[(2-pyridin-2-ylethyl)amino]propanenitrile in the form of a yellow oil(25.6 g, 96% yield).

A solution of this oil (15.3 g) in methanol saturated with ammonia (250ml) is hydrogenated in the presence of Raney nickel (1.5 g) atapproximately 20° C. for 15 hours. The reaction mixture is then filteredon Celite. The filtrate is concentrated under reduced pressure atapproximately 40° C. in order to produce the expected compound in theform of a greenish oil (15.5 g, yield 97%).

The following compounds were prepared in a similar manner to theprocedure described for the synthesis ofN-(2-pyridin-2-ylethyl)propane-1,3-diamine:

2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone

Resin-supported pyridine hydrobromide perbromide (23, g, 1 eq) is addedto a solution of 3,4,5-trimethoxy-acetophenone (10 g, 1 eq) in methanol(150 ml). After stirring for 3 hours at approximately 20° C., themixture is filtered and the filtrate is concentrated under reducedpressure. Purification of the residue obtained by flash chromatographyon silica gel (eluent: heptane/ethyl acetate 8/2 then 7/3) produces theexpected compound in the form of a white powder (8.2 g, 60% yield).Melting point=66° C.

3,4,5-trimethoxybenzoyl isothiocyanate

Potassium thiocyanate is added to a solution of3,4,5-trimethoxybenzoylchloride (2.3 g) in acetonitrile (40 ml). Afterstirring for 15 minutes at approximately 20° C., the mixture is filteredand the filtrate is concentrated under reduced pressure in order toproduce the expected compound in the form of a beige powder (2.4 g, 96%yield). Melting point=101° C.

The compounds I (or I′) of the present invention have usefulpharmacological properties. In this way it was discovered that thecompounds I (or I′) of the present invention have an antagonist activityof GnRH (Gonadotropin-Releasing hormone.

The compounds of the present invention can thus be used in differenttherapeutic applications. They can advantageously be used in women inthe treatment of endometriosis, fibroma, polycystic ovary syndrome,cancer of the breast, the ovary and the endometrium, gonadotropichypophyseal desensitization during medically-assisted procreationprotocols; in men, in the treatment of benign prostatic hyperplasia andprostate cancer; and in the treatment of male or female precociouspuberty. An illustration of the pharmacological properties of thecompounds of the invention will be found below, in the experimentalpart.

A subject of the invention is also, as medicaments, the products offormula I (or I′) as defined above, as well as the addition salts withpharmaceutically acceptable mineral or organic acids of said products offormula I (or I′), as well as the pharmaceutical compositionscontaining, as active ingredient, at least one of the medicaments asdefined above, in combination with a pharmaceutically acceptablesupport.

The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, gelatin capsules or suppositories.Appropriate solid supports can be, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound according to theinvention can also be presented in liquid form, for example solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or glycols,similarly their mixtures, in varying proportions, in water with addedpharmaceutically acceptable oils or fats. The sterile liquidcompositions can be used for intramuscular, intraperitoneal orsubcutaneous injections and the sterile compositions can also beadministered intravenously.

All the technical and scientific terms used in the present text have themeanings known to a person skilled in the art. Moreover, all patents (orpatent applications) as well as other bibliographical references areincorporated by way of reference.

Experimental Part:

The compounds according to the invention, obtained according to theprocedures of Examples A, B, C, D, E, F, G and H described previously,are set out in the table below.

The compounds are characterised by their retention time (rt) and theirmolecular peak determined by mass spectrometry (MH+).

For the mass spectrometry, a single quadripole mass spectrometer(Micromass, Platform model) equipped with an electrospray source is usedwith a resolution of 0.8 Da at 50% valley. Calibration is carried outmonthly between masses 80 and 1000 Da using a calibration mixture ofsodium iodide and rubidium iodide in solution in an isopropanol/watermixture (1/1 Vol.).

For the liquid chromatography, a Waters system including an in-linedegasser, a Waters 600 quaternary pump, a Gilson 233 plate samplinginjector and a Waters 996 PDA UV detector, are used.

The elution conditions used are the following:

-   Eluent A water+0.04% trifluoroacetic acid    -   B acetonitrile

T (min) A % B % 1 95 5 8.5 5 95 10.5 5 95 10.6 95 5 14.9 95 5 15.0 95 5

-   Flow rate: 1 ml/min-   Injection: 10 μL-   Column: Uptisphere ODS 3 μm 75*4.6 mm i.d

These examples are presented in order to illustrate the above proceduresand should in no case be considered as limiting the scope of theinvention.

In each illustration of the R₁, R₂, R₃ and R₄ radicals, the X₁, X₂, X₃and X₄ radicals represent, respectively, the remaining part of thecompound of general formula (I).

Examples 1 to 253, 254 to 255 and 256 to 538 illustrate respectivelycompounds I in which A represents —C(O)— and Y—S—, A represents —CH₂—and Y—NH— and A represents —C(O)— and Y—NH—.

Examples R1 R2 R3 R4 [M + H]⁺ rt (min) 1

599.4 9.7 2

735.3 10.7 3

600.4 9.3 4

599.5 9.1 5

579.5 9.2 6

644.5 9.1 7

649.5 9.7 8

659.5 9.2 9

667.4 9.8 10

670.5 9.7 11

640.5 9.4 12

657.5 8.9 13

677.4 9.4 14

627.5 9.6 15

681.5 9.5 16 H

634.5 7.2 17 H

614.5 7.2 18 H

679.5 7.3 19 H

684.5 7.7 20 H

694.5 7.3 21 H

702.4 7.7 22 H

705.5 7.6 23 H

673.5 7.3 24 H

692.5 7.3 25 H

712.4 7.5 26 H

662.5 7.6 27 H

716.22 7.4 28

600.5 8.5 29

580.5 8.5 30

645.5 8.5 31

650.5 9.1 32

660.6 8.5 33

668.5 9.2 34

671.2 9.0 35

641.3 8.7 36

658.5 8.4 37

678.4 8.9 38

628.5 8.9 39

682.5 8.9 40

639.4 9.6 41

571.5 9.1 42

627.5 10.2 43

649.4 9.6 44

607.5 9.5 45

621.5 9.6 46

646.5 9.2 47

747.5 9.5 48

649.4 9.6 49

629.5 9.1 50

596.4 8.9 51

605.4 9.5 52

631.5 9.2 53 H

674.3 7.5 54 H

606.4 7.3 55 H

662.5 8.0 56 H

684.3 7.5 57 H

620.4 7.4 58 H

656.4 7.6 59 H

681.4 7.4 60 H

781.3 7.7 61 H

684.3 7.5 62 H

664.4 7.3 63 H

631.4 7.2 64 H

640.4 7.5 65 H

666.4 7.3 66

640.4 9.1 67

572.4 8.5 68

628.5 9.7 69

650.4 9.0 70

586.4 8.9 71

622.5 9.1 72

647.5 8.7 73

748.5 9.1 74

650.4 9.0 75

630.4 8.6 76

597.4 8.4 77

606.4 8.9 78

632.5 8.6 79

605.5 9.0 80

666.5 9.5 81 H

577.3 8.7 82 H

515.4 8.1 83

515.4 8.1 84 H

529.5 8.4 85

557.4 8.0 86 H

569.5 8.9 87 H

583.5 9.2 88 H

607.5 8.7 89 H

599.5 9.8 90

628.5 8.4 91

652.5 7.6 92

645.5 9.7 93

660.6 9.9 94

603.4 9.1 95 H

621.4 8.7 96 H

583.4 8.7 97

674.5 8.7 98 H

605.5 9.1 99 H

669.4 9.3 100

624.5 7.2 101 H

653.5 9.5 102 H

543.5 8.6 103 H

583.5 9.2 104

598.5 7.2 105

702.5 8.0 106

676.5 7.5 107

692.5 9.0 108 H

645.4 9.5 109 H

605.5 9.2 110

629.0 9.4 111

668.0 9.8 112

659.0 9.4 113

657.0 10.4 114

689.0 9.3 115

676.8 9.5 116

626.9 9.7 117

638.9 9.5 118

654.9 9.7 119 H

692.9 8.3 120 H

723.8 7.7 121 H

711.7 7.8 122 H

661.9 7.9 123 H

673.9 7.8 124 H

689.9 8.0 125

629.9 8.9 126

669.0 9.3 127

659.9 8.9 128

658.0 9.9 129

690.0 8.8 130

677.8 9.1 131

628.0 9.1 132

640.0 9.1 133

655.9 9.3 134 H

607.0 9.8 135 H

609.0 9.6 136 H

619.0 10.1 137 H

621.0 9.1 138 H

639.0 10.0 139 H

653.0 9.1 140 H

602.0 9.0 141 H

620.0 8.6 142 H

654.9 10.0 143 H

731.9 9.4 144 H

661.1 7.9 145 H

630.0 9.1 146 H

680.0 10.1 147

626.9 9.2 148

653.9 8.8 149 H

660.0 8.0 150

662.0 9.2 151

662.9 9.1 152

638.0 7.8 153

658.9 9.3 154

689.9 9.3 155

633.0 7.8 156 H

598.0 7.8 157

683.0 7.8 158

666.0 8.1 159

674.0 8.2 160

679.9 8.2 161

660.0 8.2 162 H

586.0 7.8 163

666.0 8.4 164

667.0 7.5 165

624.0 7.9 166

633.9 8.7 167

725.0 9.5 168

700.9 9.8 169

585.0 9.5 170

674.9 9.7 171

648.8 9.7 172

726.0 9.1 173

701.9 9.4 174

585.9 9.1 175

675.9 9.3 176

649.8 9.2 177

687.5 9.3 178

716.5 9.3 179

675.5 9.3 180

676.5 8.8 181

655.5 10.4 182

684.5 10.4 183

643.5 10.4 184

662.5 8.9 185

569.5 9.1 186 H

571.5 9.3 187

696.3 7.8 188

700.3 8.7 189

674.2 7.6 190

679.1 8.4 191 H

634.2 9.5 192

705.2 8.6 193

717.1 9.9 194 H

693.2 8.8 195

689.2 7.8 196

741.2 8.0 197

654.2 9.4 198

692.4 8.4 199

H

629.1 7.9 200

713.2 9.0 201

H

651.2 7.8 202

H

656.2 9.5 203

720.3 7.5 204

663.2 7.9 205

685.2 8.5 206

689.3 8.0 207

H

654.3 10.1 208

725.3 9.3 209

737.3 10.4 210

H

713.4 9.4 211

709.4 8.3 212

761.3 8.54 213

674.3 9.9 214

H

649.3 8.5 215

733.3 9.5 216

H

671.3 8.3 217

H

676.3 10.1 218

740.4 7.9 219

683.3 8.4 220

705.3 9.2 221

709.4 8.5 222

713.3 10.0 223

708.2 10.0 224

H

669.4 8.2 225

H

708.3 9.6 226

H

663.3 8.1 227

H

671.4 8.2 228

H

696.3 9.8 229

H

706.4 10.3 230

622.2 9.3 231

678.2 10.4 232

H

649.3 7.3 233

H

660.3 8.5 234

660.4 7.3 235

H

663.4 7.3 236

H

690.5 9.2 237

729.5 7.4 238

H

691.4 7.4 239

H

669.4 7.5 240

H

686.4 7.4 241

H

621.3 7.3 242

H

675.4 7.4 243

H

663.4 7.4 244

H

634.4 8.2 245

H

677.4 7.4 246

H

691.4 7.4 247

718.6 9.5 248

677.5 7.4 249

657.4 11.4 250

685.4 11.7 251

557.3 8.6 252

585.3 8.8 253

617.2 12.4 254

617.4 7.2 255

617.4 7.1 256

568.4 8.4 257

568.3 7.8 258

600.4 7.8 259 H

747.5 6.7 260

601.4 7.4 261

574.4 8.3 262

590.4 8.2 263

615.4 8.6 264

568.5 8.1 265

582.4 8.0 266

582.5 8.5 267

576.4 8.1 268

565.4 8.1 269

584.4 8.0 270

580.5 8.3 271

632.4 8.6 272

632.4 8.5 273 H

609.3 7.0 274 H

625.4 7.0 275 H

650.4 7.2 276 H

603.4 6.9 277 H

617.4 6.8 278 H

617.4 7.2 279 H

611.4 6.8 280 H

600.4 6.9 281 H

619.3 6.7 282 H

615.4 7.0 283 H

667.4 7.3 284 H

667.3 7.2 285

575.4 7.6 286

591.4 7.5 287

616.4 7.9 288

569.4 7.4 289

583.4 7.4 290

583.4 7.8 291

577.4 7.4 292

566.4 7.5 293

583.3 7.3 294

581.4 7.6 295

633.3 7.9 296

633.2 7.8 297

570.1 7.9 298

600.1 7.9 299

586.1 8.0 300

604.1 8.4 301

583.2 7.9 302

600.1 8.0 303

586.1 8.3 304

570.1 7.9 305

570.1 8.1 306

584.1 8.0 307

571.1 7.6 308

601.1 7.6 309

586.9 7.6 310

605.0 8.1 311

584.1 7.6 312

601.1 7.7 313

587.0 7.9 314

571.1 7.6 315

571.1 7.7 316

585.1 7.7 317 H

540.4 8.1 318

593.2 7.4 319

597.2 7.9 320

626.2 8.7 321

528.2 8.0 322 H

552.2 8.6 323

623.3 8.1 324

635.2 8.8 325 H

611.2 8.2 326

607.0 7.6 327

659.2 7.8 328

572.2 8.5 329 H

547.2 7.7 330

631.2 8.4 331 H

569.2 7.6 332 H

574.2 8.6 333

638.3 7.4 334

581.3 7.7 335

603.2 8.0 336

607.3 7.7 337 H

585.2 8.18 338

656.3 7.2 339

668.2 8.4 340 H

644.2 7.8 341

640.3 7.2 342

692.2 7.5 343

605.2 8.1 344 H

580.2 7.3 345

664.2 8.0 346 H

602.3 7.2 347 H

607.2 8.21 348

671.3 7.1 349

614.3 7.3 350

636.2 7.6 351

640.3 7.4 352

538.2 8.2 353 H

555.3 7.5 354 H

567.3 7.4 355 H

620.3 8.1 356 H

547.3 7.4 357

602.3 7.5 358 H

564.3 7.4 359 H

614.2 8.5 360 H

619.3 8.1 361

689.3 7.6 362

652.3 7.5 363 H

648.3 7.3 364 H

614.3 7.3 365 H

599.2 7.9 366 H

605.3 8.0 367

670.4 8.1 368

645.5 8.0 369

629.5 8.0 370

631.3 7.9 371

584.5 8.5 372

598.5 8.4 373

628.5 8.2 374

563.5 8.7 375

613.5 8.3 376

627.6 8.3 377

657.6 8.1 378

592.5 8.4 379

572.5 8.4 380

586.5 8.3 381

616.5 8.1 382

551.5 8.6 383

573.4 8.0 384

587.5 8.0 385

617.5 7.8 386

552.5 8.1 387

587.5 8.1 388

601.5 8.0 389

631.5 7.9 390

566.5 8.2 391

599.4 8.9 392

626.4 9.3 393

598.3 9.0 394

635.5 8.1 395

599.4 7.9 396

635.4 8.0 397

603.4 8.9 398

603.4 9.3 399

603.4 9.3 400

614.4 9.1 401

583.5 8.9 402

583.5 9.1 403

583.5 9.1 404

569.4 8.9 405

556.4 7.6 406

601.4 7.8 407

659.5 8.8 408

508.4 7.9 409

538.4 7.8 410

537.4 7.9 411

567.4 7.8 412

506.4 7.3 413

496.4 7.9 414

526.4 7.8 415

465.4 7.3 416

498.3 7.7 417

526.3 7.8 418

631.4 7.5 419

618.5 8.2 420

594.4 8.1 421

594.5 8.3 422

589.4 7.8 423

588.4 8.2 424

632.4 8.2 425

568.4 8.1 426

631.5 8.2 427

580.5 8.2 428

596.5 8.0 429

659.6 8.1 430

655.5 8.1 431

608.6 8.1 432

618.5 8.1 433

572.4 7.7 434

648.5 8.3 435

652.5 8.1 436

616.4 8.0 437

644.4 8.2 438

650.4 8.1 439

641.4 8.0 440

694.3 8.2 441

622.3 8.0 442

622.5 8.2 443

582.4 8.0 444

624.4 8.3 445

612.4 9.2 446

512.2 7.7 447

602.4 8.0 448

608.4 8.1 449

645.4 8.0 450

671.5 8.3 451

687.5 8.3 452

552.3 8.3 453

552.3 8.0 454

538.3 8.4 455

560.2 9.1 456

594.4 8.1 457

674.5 8.4 458

603.4 7.9 459

603.4 7.8 460

603.4 7.7 461

554.4 7.9 462

568.4 8.0 463

600.3 8.0 464

582.4 8.1 465

596.4 8.2 466

582.4 8.1 467

566.3 7.9 468

606.4 8.2 469

582.4 8.1 470

596.4 8.2 471

0.0 0.0 472

568.4 8.0 473

582.3 7.8 474

595.4 7.8 475

594.4 7.9 476

566.3 7.8 477

580.3 7.9 478

594.4 8.1 479

612.4 8.0 480

616.4 8.2 481

618.4 7.9 482

632.4 8.1 483

680.3 8.3 484

692.4 8.1 485

580.3 8.1 486

646.4 8.1 487

662.4 8.0 488

658.5 8.5 489

659.4 7.9 490

627.4 8.1 491

638.4 8.0 492

580.4 8.0 493

646.4 8.2 494

638.5 8.7 495

614.4 8.1 496

652.4 8.3 497

636.4 8.2 498

630.4 8.3 499

660.4 8.1 500

662.4 8.2 501

644.4 8.4 502

608.4 8.2 503

616.4 8.2 504

630.4 8.3 505

554.4 7.8 506

672.4 8.6 507

584.4 7.9 508

568.3 7.9 509

596.4 8.1 510

612.4 8.0 511

582.4 8.1 512

556.3 7.9 513

598.3 7.9 514

580.4 8.0 515

552.3 7.9 516

612.4 8.0 517

606.4 8.2 518

624.4 8.4 519

612.4 8.0 520

646.4 8.3 521

608.4 8.2 522

616.3 8.2 523

630.3 8.2 524

636.4 8.5 525

608.3 8.2 526

582.3 8.1 527

600.3 7.8 528

610.3 8.2 529

582.3 8.1 530

598.3 7.9 531

584.3 7.9 532

570.2 7.8 533

596.4 8.2 534

610.3 7.9 535

586.3 8.4 536

534.3 7.6 537

540.3 7.9 538

586.3 8.4Pharmacological Study

The antagonist activity of the GnRH of the compounds according to theinvention is measured according to the following protocols:

Establishment of a Stable Line Transfected by the Human LHRH Receptor:

The cDNA of the human LHRH receptor is cloned in the EcoRI site in amammalian expression vector pCDNA3.1 (InVitrogen Inc.). This plasmidconstruction is transfected using Effectene according to themanufacturers recommendations (Qiagen) in a cell line derived from humanembryo kidney, HEK-293 (ATCC) and the selection is carried out in a DMEMmedium containing 0.5 mg/ml of geneticin. The cells containing theexpression vector for the LHRH receptor are then cloned by limiteddilution then multiplied in culture. These cell clones are then testedfor the expression of the human LHRH receptor by competitive inhibitiontests of the bond and measurement of inositol phosphates.

Cell Culture and Membrane Preparation:

The HEK-293 cells expressing in a stable manner the human LHRH receptoras described above are cultured in a DMEM medium in the presence of 10%foetal calf serum and supplemented by 0.4 mg/ml geneticin (G418, SigmaChemical Company). The cells are detached from the culture medium withEDTA 0.5 mM and centrifuged at 500 g for 10 minutes at 4° C. The cellpellet is washed with Tris 50 mM, pH 7.4 and centrifuged twice at 500 gfor 10 minutes. The cells are finally lysed by sonication thencentrifuged at 39000 g for 10 minutes at 4° C. The pellet is resuspendedin Tris 50 mM, pH 7.4 and centrifuged at 50000 g for 10 minutes at 4° C.in order to obtain a membrane pellet divided into several aliquotsstored at −80° C. before use.

Study of the Affinity for the Human LHRH Receptor:

The affinity of a compound of the invention for the human LHRH receptoris determined by measurement of the inhibition of the bond of[¹²⁵I-Tyr5]-DTrp⁶-LHRH on human cells transfected by the cDNA of thehuman LHRH receptor.

The competitive inhibition tests of the bond of [¹²⁵I-Tyr5]-DTrp⁶-LHRHare carried out in duplicate in polypropylene 96 well plates. Themembranes of the HEK-293 cells expressing in a stable manner the humanLHRH receptor (20 μg proteins/well) are incubated in the presence of[¹²⁵I-Tyr5]-DTrp⁶-LHRH (0.2 nM) for 60 minutes at 4° C. in a mediumcontaining Tris/HCl 50 mM pH 7.4, Bacitracin 0.1 mg/ml, BSA 0.1% (1mg/ml).

The bound [¹²⁵I-Tyr5]-DTrp⁶-LHRH is separated from the free[¹²⁵I-Tyr5]-DTrp⁶-LHRH by filtration through filter plates constitutedby glass fibre GF/C (Unifilter, Packard) impregnated withpolyethylenimine 0.1%, using a FilterMate 96 (Packard). The filters arethen washed with Tris/HCl 50 mM buffer at 4° C. for 4 seconds and theradioactivity is counted using a scintillation counter (Packard,Topcount).

The specific bond is calculated after subtracting the non-specific bond(determined in the presence of DTrp⁶-LHRH 0.1 μM) from the total bond.The data relative to the bond obtained by nonlinear regression analysisand the inhibition constant values (Ki) are determined.

Determination of the agonist or antagonist profile of a compound of thepresent invention is carried out by the method described below.

Functional Test: Inhibition of the Production of Intracellular InositolPhosphates

HEK-293 cells expressing in a stable manner the human GnRH receptor arecultured at a rate of 200,000 cells per well in a 24-well plate coatedwith poly-D-lysine (Falcon Biocoat) in a DMEM medium in the presence of10% foetal calf serum and 0.4 mg/ml geneticin for 24 hours.

The medium is then replaced by DMEM not containing Inositol in thepresence of 10% foetal calf serum and 1 μCi/ml of [3H]myo-inositol(Amersham) for 16-18 hours at 37° C.

The cells are washed with DMEM not containing inositol in the presenceof 10 mM lithium chloride and incubated for 30 minutes at 37° C.

The production of inositol phosphates is stimulated by the addition ofDTrp⁶-LHRH 0.5 nM over 45 minutes at 37° C.

The antagonist effect of a compound is measured by the simultaneousaddition of 6 DTrp⁶-LHRH 0.5 nM and the compounds to be tested atdifferent increasing concentrations (example: 10⁻¹⁰ M to 10⁻⁵M).

The reaction medium is eliminated and 1 ml of 0.1 M formic acid is addedand incubated for 5 minutes at 4° C.

The plate is then frozen at −80° C. then thawed at ambient temperature.

The inositol phosphates are then separated from all of the intracellularinositols on ion exchange resin (Biorad) by eluting with 1M ammoniumformate and 0.1M formic acid.

The quantity of inositol phosphates leaving the column is finallymeasured in the presence of scintillating liquid.

Results:

The tests carried out according to the protocols described above haveallowed it to be shown that the products of general formula (I) definedin the present Application have a good affinity for the LHRH receptor,the inhibition constant K_(i) on this receptor being below micromolarfor certain of the exemplified compounds.

1. A compound of the formula

in racemic, enantiomeric form or any combination of these forms wherein:A is —CH₂— or —C(O)—; Y is —S— or —NH—; R₁ and R₂ are independentlyselected from the group consisting of hydrogen, (C₁-C₈)alkyl,(C₅-C₉)bicycloalkyl optionally substituted by at least one (C₁-C₆)alkyl,and —(CH₂)_(n)—X, X is selected from the group consisting of amino,(C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl, adamantly,heterocycloalkyl, aryl, aryl-carbonyl, heteroaryl,

the (C₃-C₇)cycloalkyl, heterocycloalkyl aryl and heteroaryl beingoptionally substituted by at least one member selected from the groupconsisting of —(CH₂)_(n′)—X′—Y′, halo, oxo, nitro, cyano, amino,(C₁-C₆)alkylamino, di((C₁-C₈)alkyl)amino, hydroxy and N₃; X′ is selectedfrom the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—,—NH—SO₂— and a covalent bond; Y′ is selected from the group consistingof (C₁-C₆)alkyl optionally substituted by at least one halo; heteroaryl,aryl and heterocycloalkyl optionally substituted by at least one memberselected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,nitro, cyano, amino, CF₃, OCF₃, hydroxy, N₃, (C₁-C₆)alkylamino anddi((C₁-C₈)alkyl)amino; n is an integer from 0 to 6 and n′ is an integerfrom 0 to 2; or R₁ and R₂ form together with the nitrogen atom to whichthey are attached, a member selected from the group consisting ofheterocycloalkyl, heterobicycloalkyl,

the member which R₁ and R₂ together form is optionally substituted by atleast one member selected from the group consisting of—(CH₂)_(n″)—X″—Y″, oxo, hydroxy, halo, nitro and cyano; X″ is selectedfrom the group consisting of —O—, —C(O)—, —C(O)—O— and a covalent bond;Y″ is selected from the group consisting of (C₁-C₆)alkyl, amino,(C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl,heterocycloalkyl, arylalkyl, aryl and heteroaryl optionally substitutedby at least one member selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-carbonyl, halo, hydroxy,nitro, cyano, CF₃, OCF₃, amino, (C₁-C₆)alkylamino,di((C₁-C₆)alkyl)amino),

n″ is an integer from 0 to 4; R₃ is —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃ W₃ isselected from the group consisting of a covalent bond, —CH(OH)— and—C(O)—; Z₃ is selected from the group consisting of (C₁-C₆)alkyl,adamantly, aryl, a heteroaryl,

the aryl being optionally substituted by at least one member selectedfrom the group consisting of —(CH₂)_(p″)—V₃—Y₃, halo, nitro, cyano, N₃,and hydroxy; V₃ is selected from the group consisting of —O—, —S—,—C(O)—, —C(O)—O—, —SO₂— and a covalent bond; Y₃ is selected from thegroup consisting of (C₁-C₆)alkyl optionally substituted by at least onemember selected from the group consisting of halo, amino,(C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, phenylcarbonylmethyl,heterocycloalkyl and aryl; p, p′ and p″ represent are, independently, aninteger from 0 to 4; R₄ is —(CH₂)_(s)—R″₄ R″₄ is selected from the groupconsisting of heterocycloalkyl containing at least one nitrogen atom andoptionally substituted by (C₁-C₆)alkyl or aralkyl; a heteroarylcontaining at least one nitrogen atom and optionally substituted by(C₁-C₆)alkyl; and —NW₄W′₄ W₄ is selected from the group consisting ofhydrogen, (C₁-C₈)alkyl and (C₃-C₇)cycloalkyl; W′₄ is —(CH₂)_(s)-Q₄-Z₄;Q₄ is selected from the group consisting of a covalent bond,—CH₂—CH(OH)—[CH₂]_(t)—[O]_(t′)—[CH₂]_(t″) and —C(O)—O—; t, t′ and t″are, independently, 0 or 1; Z₄ is selected from the group consisting ofhydrogen, (C₁-C₈)alkyl optionally substituted by at least one memberselected from the group consisting of (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₁-C₆)alkyldithio, hydroxy; (C₂-C₆)alkenyl; (C₂-C₆)alkynyl;(C₃-C₇)cycloalkyl optionally substituted by at least one member selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy-carbonyl and(C₁-C₆)hydroxyalkyl; cyclohexene, adamantyl; heteroaryl and aryloptionally substituted by at least one member selected from the groupconsisting of —(CH₂)_(q″)—V₄—Y₄, hydroxy, halo, nitro and cyano; V₄ isselected from the group consisting of —O—, —S—, —NH—C(O)— and a covalentbond; Y₄ is selected from the group consisting of (C₁-C₆)alkyloptionally substituted by di((C₁-C₆)alkyl)amino or at least one halo;amino; (C₁-C₆)alkylamino; di((C₁-C₆)alkyl)amino; aralkyl andheterocycloalkyl; q″ represents is an integer from 0 to 4; or Z₄ is

s and s′ are, independently, an integer from 0 to 6; and apharmaceutically acceptable salt thereof.
 2. A compound of claim 1,wherein A is —C(O)—; or a pharmaceutically acceptable salt thereof.
 3. Acompound of claim 1 wherein cycloalkyl represented by X is cyclohexyl orcycloheptyl, the heterocycloalkyl represented by X is selected from thegroup consisting of piperidine, morpholine, pyrrolidine, thiazolidineand tetrahydrothiophene; the aryl represented by X is selected from thegroup consisting of phenyl, naphthyl and fluorenyl; the aryl of thearyl-carbonyl represented by X, is phenyl; the heteroaryl represented byX is selected from the group consisting of pyridine, imidazole,thiophene, indole, carbazole and isoquinoline; the heteroarylrepresented by Y′ is oxazole or imidazole; the aryl represented by Y′ isphenyl; the heterocycloalkyl represented by Y′ is piperazine; theheterocycloalkyl which R₁ and R₂ form together with the nitrogen atom towhich they are attached, is selected from the group consisting ofpiperidine, piperazine, diazepane, thiazolidine and morpholine; thecycloalkyl represented by Y″ is cyclopentyl or cyclohexyl; theheterocycloalkyl represented by Y″ is selected from the group consistingof piperidine, pyrrolidine and morpholine; the arylalkyl and the arylrepresented by Y″ are respectively benzyl and phenyl; the heteroarylrepresented by Y″ is selected from the group consisting of pyridine,pyrazine, furan and thiophene; or a pharmaceutically acceptable saltthereof.
 4. A compound of claim 1 wherein the aryl represented by Z₃ isthe phenyl or naphthyl; the heteroaryl represented by Z₃ isbenzo[b]thiophene or benzo[b]furan; the heteroaryl represented by Z₃ isbenzo[b]thiophene or benzo[b]furan; the heterocycloalkyl and the arylrepresented by Y₃ are respectively pyrrolidine and phenyl or apharmaceutically acceptable salt thereof.
 5. A compound of claim 1wherein the heterocycloalkyl represented by R″₄ is selected from thegroup consisting of piperazine, piperidine, morpholine and pyrrolidine;the aralkyl which optionally substitutes the heterocycloalkylrepresented by R″₄ is benzyl; the heteroaryl represented by R″₄ isimidazole; the (C₃-C₇)cycloalkyl represented by Z₄ is selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; the heteroaryl represented by Z₄ is selected from the groupconsisting of pyridine, thiophene, indole and furan; the arylrepresented by Z₄ is phenyl or naphthyl; the aralkyl represented by Y₄is benzyl; the heterocycloalkyl represented by Y₄ is pyrrolidine; thearalkyl which is substituted on the heterocycloalkyl formed together byW₄ and W′₄ is benzyl; or a pharmaceutically acceptable salt thereof. 6.A compound of claim 1 wherein A is —C(O)— and R₁ and R₂ areindependently selected from the group consisting of hydrogen,((C₁-C₈)alkyl and —(CH₂)_(n)—X in which X is selected from the groupconsisting of amino, di(alkyl)amino, adamentyl, cyclohexyl, cycloheptyl,piperidine, morpholine, pyrrolidine, phenyl, pyridine, imidazole,thiophene, indole, carbazole being optionally substituted by(C₁-C₆)alkyl,

the piperidine, pyrrolidine and phenyl being optionally substituted byat least one member selected from the group consisting of—(CH₂)_(n′)—X′—Y′, halo, oxo, amino and di((Ci —C₈)alkyl)amino; X′ isselected from the group consisting of —O—, —S—, —C(O)—O—, —NH—C(O)—,—NH—SO₂— and a covalent bond; Y′ is selected from the group consistingof (C₁-C₆)alkyl, oxazole, phenyl optionally substituted by (C₁-C₄)alkylor piperazine optionally substituted by (C₁-C₄)alkyl; or R₁ and R₂ formtogether with the nitrogen atom to which they are attached, a memberselected from the group consisting of piperidine, piperazine, diazepane,thiazolidine, morpholine,

the member formed by R₁ and R₂ together being optionally substituted byat least one—(CH₂)_(n″)—X″—Y″; X″ is selected from the group consisting of —C(O)—,—C(O)—O— or a covalent bond; Y″ is selected from the group consisting of(C₁-C₆)alkyl; di(alkyl)amino, cyclopentyl, cyclohexyl, piperidine,pyrrolidine, morpholine, benzyl, pyridine, pyrazine, furan, thiophene,and phenyl optionally substituted by at least one member selected fromthe group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkyl-carbonyl and halo; or Y″

or a pharmaceutically acceptable salt thereof.
 7. A compound of claim 1wherein A is —C(O)— and R₃ is —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃ W₃ is selectedfrom the group consisting of a covalent bond, —CH(OH)— and —C(O)—; Z₃ isselected from the group consisting of (C₁-C₆)alkyl, phenyl, naphthyl,benzo[b]thiophene, benzo[b]furannyl,

the phenyl radical being optionally substituted by at least one memberselected from the group consisting of —(CH₂)_(p″)—V₃—Y₃, halo, nitro,cyano; V₃ is —O—, —S—, —C(O)—, —C(O)—O—, —SO₂— and a covalent bond; Y₃is selected from the group consisting of (C₁-C₆)alkyl radical optionallysubstituted by at least one halo; amino; di((C₁-C₆)alkyl)amino;phenylcarbonylmethyl; pyrrolidine and phenyl; p, p′ and p″ areindependently, an integer from 0 to 2; or a pharmaceutically acceptablesalt thereof.
 8. A compound of A compound of claim 1 wherein A is —C(O)—and R₄ is —(CH₂)_(s)—R″₄ R″₄ is selected from the group consisting ofpiperidine ring optionally substituted by benzyl, piperazine optionallysubstituted by benzyl and —NW₄W′₄ W₄ is hydrogen or (C₁-C₈)alkyl; W′₄ is—(CH₂)_(s)-Q₄-Z₄; Q₄ is selected from the group consisting of a covalentbond, —CH₂—CH(OH)—, —CH₂—CH(OH)—CH₂—O—, —CH₂—CH(OH)—CH₂—,—CH₂—CH(OH)—CH₂—O—; CH₂ and —C(O)—O—; Z₄ is selected from the groupconsisting of hydrogen, (C₁-C₈)alkyl optionally substituted by(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkyldithio, one or two hydroxy;(C₂-C₆)alkenyl; (C₂-C₆)alkynyl; cyclopropyl optionally substituted byalkoxycarbonyl; cyclobutyl, cyclopentyl optionally substituted byhydroxyalkyl; cyclohexyl optionally substituted by at least one alkyl;cycloheptyl, cyclohexene, adamantyl, pyridine, thiophene, indole,furane, naphthyl; phenyl optionally substituted by at least one memberselected from the group consisting of —(CH₂)_(q″)—X₄—Y₄, hydroxy, haloand cyano; X₄ is —O— or a covalent bond; Y₄ is selected from the groupconsisting of (C₁-C₆)alkyl, di((C₁-C₆)alkyl)amino and pyrrolidine or apharmaceutically acceptable salt thereof.
 9. A compound of claim 1wherein A is —C(O)—, Y is —NH— and R₁ and R₂ are independently(C₁-C₈)alkyl; R₃ is —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃ W₃ is a covalent bond;Z₃ is phenyl substituted by at least one member selected from the groupconsisting of —(CH₂)_(p″)—V₃—Y₃ and halo; V₃ is —O— or —S—; and Y₃ is(C₁-C₆)alkyl; p, p′ and p″ are 0; R₄ is —(CH₂)_(s)—R″₄ R″₄ is —NW₄W′₄ W₄is hydrogen or (C₁-C₈)alkyl; W′₄ is —(CH₂)_(s′)-Q₄-Z₄; Q₄ is a covalentbond; Z₄ is selected from the group consisting of hydrogen,(C₁-C₈)alkyl, optionally substituted by hydroxy, (C₃-C₇)cycloalkyl,heteroaryl, aryl optionally substituted by at least one—(CH₂)_(q″)—V₄—Y₄; V₄ is —O— or a covalent bond; Y₄ is (C₁-C₆)alkyl ordi((C₁-C₆)alkyl)amino; q″ represents is 0; s is an integer from 2 to 4,and s′ is an integer from 1 to 2; or a pharmaceutically acceptable saltthereof.
 10. A compound of claim 9, wherein (C₃-C₇)cycloalkyl iscyclopentyl or cyclohexyl, the heteroaryl is pyridine and the aryl isphenyl; or a pharmaceutically acceptable salt thereof.
 11. A compound ofclaim 1 wherein A is —C(O)—, Y is sulfur, R₁ and R₂ are independently(C₁-C₈)alkyl; R₃ is —(CH₂)_(p)—W₃—(CH₂)_(p′)-Z₃ W₃ is a covalent bond or—C(O)—; Z₃ is phenyl substituted by at least one of —(CH₂)_(p″)—V₃Y₃ orhalo; V₃ is —O— or a covalent bond; and Y₃ is (C₁-C₆)alkyl ordi((C₁-C₆)alkyl)amino; p is 1, and p′ and p″ are 0; R₄ is —(CH₂)_(s)—R″₄R″₄ is —NW₄W′₄ W₄ is hydrogen or (C₁-C₈)alkyl; W′₄ is —(CH₂)_(s′)-Q₄-Z₄;Q₄ is a covalent bond; Z₄ is selected from the group consisting ofhydrogen, (C₁-C₈)alkyl, heteroaryl and aryl s is an integer from 2 to 4,and s′ is an integer from 1 to 2, or a pharmaceutically acceptable saltthereof.
 12. A compound of claim 11, wherein heteroaryl is pyridine andaryl is phenyl; or a pharmaceutically acceptable salt thereof.
 13. Acompound of claim 1, wherein A is selected from the group consisting of—CH₂—, or Y—NH— and R₁ and R₂ are independently ((C₁-C₆)alkyl; R₃ isphenyl substituted by at least one (C₁-C₆)alkoxy; R₄ is —(CH₂)_(s)—R″₄;R″₄—NW₄W′₄; W₄ is (C₁-C₈)alkyl; W′₄—(CH₂)_(s′)-Q₄-Z₄; Q₄ is a covalentbond and Z₄ is pyridine; or a pharmaceutically acceptable salt thereof.14. A composition with antagonist activity to Gonadotropin-Releasinghormone comprising an antagonistically effective amount of a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 15. A method oftreating women during medically-assisted procreation protocols forendometriosis, fibroma, polycystic ovary syndrome, breast cancer, ovarycancer, endometrium cancer and gonadotropic hypophyseal desensitizationcomprising administering to women in need thereof an amount of acompound of claim 1 sufficient to treat said condition.
 16. A method oftreating men for benign prostatic hyperplasia and prostate cancercomprising administering to men in need thereof an amount of a compoundof claim 1 sufficient to treat said conditions.
 17. A method of treatinga youngster for precocious male or female puberty comprisingadministering to a youngster in need thereof an amount of a compound ofclaim 13 sufficient to treat said condition.